Histone demethylase inhibitors

ABSTRACT

The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyrido[3,4-d]pyrimidin-4-one derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

CROSS REFERENCE

This application is a division of U.S. patent application Ser. No.14/855,950, filed Sep. 16, 2015 (now U.S. Pat. No. 9,643,965), whichclaims the benefit of U.S. Provisional Application No. 62/051,691 filedSep. 17, 2014, the content of which is hereby incorporated by referencein its entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted pyrido[3,4-d]pyrimidin-4-one derivativecompounds and pharmaceutical compositions comprising said compounds. Thesubject compounds and compositions are useful for inhibition histonedemethylase. Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, bladder cancer, lung cancer and/or melanoma and the like. Thesubstituted pyrido[3,4-d]pyrimidin-4-one derivative compounds describedherein are based upon a substituted pyrido[3,4-d]pyrimidin-4-one ringsystem bearing a hydroxy group at the 4-position, and an oxygen-basedsubstituent at the 2-position.

One embodiment provides a compound of Formula (I), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is —O—, —S—, —SO₂—, —CF₂—, —(CH₂)—N(H)—, —(CH₂)—N(H)—(C═O)—,—(CH₂)—N(C₁-C₃alkyl)-(C═O)—; andZ is aryl, carbocyclyl, or heterocyclyl.

One embodiment provides a compound of Formula (II), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;ring B is chosen from:

Y is C₁-C₃alkyl; andZ is aryl or heteroaryl.

One embodiment provides a compound of Formula (III), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen or C₁-C₃alkyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, carbocyclyl,aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, orcarbocyclylalkyl; and m is 0, 1, or 2.

One embodiment provides a compound of Formula (IV), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen or C₁-C₃ alkyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, carbocyclyl,aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, orcarbocyclylalkyl; and m is 0, 1, or 2.

One embodiment provides a compound of Formula (V), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen or C₁-C₃ alkyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, carbocyclyl,aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, orcarbocyclylalkyl; and m is 0, 1, or 2.

One embodiment provides a compound of Formula (VI), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Z is N or C—H;R is alkyl, aryl, aralkyl, or carbocyclylalkyl.

One embodiment provides a compound of Formula (VII), or pharmaceuticallyacceptable salt thereof,

wherein,A1, A2, and A3 are chosen from C—H, N or N—R, provided that at least oneof A1, A2, or A3 is C—H, and at least one of A1, A2, or A3 is N—R; andR is aryl, aralkyl, or carbocyclylalkyl.

Another embodiment provides the compound of Formula (VII), orpharmaceutically acceptable salt thereof, having a structure selectedfrom Formula (VIIa)-(VIId) as described below:

One embodiment provides a compound of Formula (VIII), orpharmaceutically acceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is C₁-C₃alkyl; andZ is aralkyl.

One embodiment provides a compound of Formula (IX), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is C₁-C₃alkyl; andZ is aralkyl.

One embodiment provides a compound of Formula (X), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;ring A, represented by

is chosen from:

andR¹ is alkyl, aryl, aralkyl, carbocyclyl, carbocyclylalkyl, —(C═O)aryl,or —(SO₂)aryl.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I)-(X), or pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable excipient.

One embodiment provides a method for inhibiting a histone demethylaseenzyme comprising contacting the histone demethylase enzyme with acompound of Formula (I)-(X).

One embodiment provides a method for treating cancer in subject in needthereof comprising administering to the subject a composition comprisinga compound of Formula (I)-(X), or a pharmaceutically acceptable saltthereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a)) C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a)) C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a)) C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a)) C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans). Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedpyrido[3,4-d]pyrimidin-4-one derivative compounds described herein isintended to encompass any and all pharmaceutically suitable salt forms.Preferred pharmaceutically acceptable salts of the compounds describedherein are pharmaceutically acceptable acid addition salts andpharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Substituted Pyrido[3,4-d]pyrimidin-4-one Derivative Compounds

Substituted pyrido[3,4-d]pyrimidin-4-one derivative compounds aredescribed herein that inhibit a histone demethylase enzyme. Thesecompounds, and compositions comprising these compounds, are useful forthe treatment of cancer and neoplastic disease. The compounds describedherein are useful for treating prostate cancer, breast cancer, bladdercancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula (I), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is —O—, —S—, —SO₂—, —CF₂—, —(CH₂)—N(H)—, —(CH₂)—N(H)—(C═O)—,—(CH₂)—N(C₁-C₃alkyl)-(C═O)—; andZ is aryl, carbocyclyl, or heterocyclyl.

Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, wherein n is 1 and X is fluoro.

Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein Y is —O—. Anotherembodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, wherein Y is —S—. Another embodiment providesthe compound of Formula (I), or pharmaceutically acceptable saltthereof, wherein Y is —SO₂. Another embodiment provides the compound ofFormula (I), or pharmaceutically acceptable salt thereof, wherein Y is—CF₂—. Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein Y is —(CH₂)N(H)(C═O)—.Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein Y is—(CH₂)—N(C₁-C₃alkyl)-.

Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein Z is aryl. Anotherembodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, wherein Z is phenyl optionally substituted withhalogen, alkyl, alkoxy, or carbocyclyl. Another embodiment provides thecompound of Formula (I), or pharmaceutically acceptable salt thereof,wherein Z is carbocyclyl. Another embodiment provides the compound ofFormula (I), or pharmaceutically acceptable salt thereof, wherein Z is1,2,3,4-tetrahydronaphthalenyl.

Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein Z is heterocyclyl.Another embodiment provides the compound of Formula (I), orpharmaceutically acceptable salt thereof, wherein Z is chromanyl.

One embodiment provides a compound of Formula (II), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;ring B is chosen from:

Y is C₁-C₃alkyl; andZ is aryl or heteroaryl.

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (II), or pharmaceuticallyacceptable salt thereof, wherein n is 1 and X is fluoro.

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein Y is C₁alkyl. Anotherembodiment provides the compound of Formula (II), or pharmaceuticallyacceptable salt thereof, wherein Y is C₂alkyl.

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein ring B is

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein ring B is

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein ring B is

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein ring B is

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein ring B is

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein Z is aryl. Anotherembodiment provides the compound of Formula (II), or pharmaceuticallyacceptable salt thereof, wherein Z is phenyl optionally substituted withalkyl, —(C═O)N(R^(a))₂, heteroaryl, or heterocyclyl; wherein each R^(a)is independently hydrogen or C₁-C₃alkyl. Another embodiment provides thecompound of Formula (II), or pharmaceutically acceptable salt thereof,wherein Z is heteroaryl.

Another embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, wherein Z is

One embodiment provides a compound of Formula (III), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen, C₁-C₃alkyl, cycloalkyl, or heterocyclyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, dialkylamino,—SO₂-alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, aralkyl,heterocyclylalkyl, heterocyclyl-(aminoalkyl)-, or carbocyclylalkyl; andm is 0, 1, or 2.

One embodiment provides a compound of Formula (III) having the structureof Formula (IIIa), or pharmaceutically acceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen or C₁-C₃alkyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, carbocyclyl,aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, orcarbocyclylalkyl; and m is 0, 1, or 2.

Another embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt thereof, wherein n is 1. Another embodiment provides thecompound of Formula (III), or pharmaceutically acceptable salt thereof,wherein X is fluoro.

Another embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt thereof, wherein Y is hydrogen. Anotherembodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt thereof, wherein Y is C₁alkyl. Another embodimentprovides the compound of Formula (III), or pharmaceutically acceptablesalt thereof, wherein Y is C₂alkyl.

Another embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt thereof, wherein m is 0. Anotherembodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt thereof, wherein m is 1. Another embodiment provides thecompound of Formula (III), or pharmaceutically acceptable salt thereof,wherein m is 2.

Another embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt thereof, wherein Z is halogen, —CN,alkyl, alkoxy, carbocyclyl, or heterocyclyl. Another embodiment providesthe compound of Formula (III), or pharmaceutically acceptable saltthereof, wherein Z is fluoro, chloro, methyl, methoxy, or morpholinyl.

One embodiment provides a compound of Formula (IV), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen or C₁-C₃ alkyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, carbocyclyl,aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, orcarbocyclylalkyl; and m is 0, 1, or 2.

Another embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (IV), or pharmaceuticallyacceptable salt thereof, wherein n is 1. Another embodiment provides thecompound of Formula (IV), or pharmaceutically acceptable salt thereof,wherein X is fluoro.

Another embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt thereof, wherein Y is hydrogen. Anotherembodiment provides the compound of Formula (IV), or pharmaceuticallyacceptable salt thereof, wherein Y is C₁alkyl. Another embodimentprovides the compound of Formula (IV), or pharmaceutically acceptablesalt thereof, wherein Y is C₂alkyl.

Another embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt thereof, wherein m is 0. Anotherembodiment provides the compound of Formula (IV), or pharmaceuticallyacceptable salt thereof, wherein m is 1. Another embodiment provides thecompound of Formula (IV), or pharmaceutically acceptable salt thereof,wherein m is 2.

Another embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt thereof, wherein Z is halogen, —CN,alkyl, alkoxy, carbocyclyl, or heterocyclyl. Another embodiment providesthe compound of Formula (IV), or pharmaceutically acceptable saltthereof, wherein Z is fluoro, chloro, methyl, methoxy, or morpholinyl.

One embodiment provides a compound of Formula (V), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is hydrogen or C₁-C₃ alkyl;Z is halogen, —OH, —NH₂, —CN, alkyl, alkoxy, alkylamino, carbocyclyl,aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, orcarbocyclylalkyl; and m is 0, 1, or 2.

Another embodiment provides the compound of Formula (V), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (V), or pharmaceuticallyacceptable salt thereof, wherein n is 1. Another embodiment provides thecompound of Formula (V), or pharmaceutically acceptable salt thereof,wherein X is fluoro.

Another embodiment provides the compound of Formula (V), orpharmaceutically acceptable salt thereof, wherein Y is hydrogen. Anotherembodiment provides the compound of Formula (V), or pharmaceuticallyacceptable salt thereof, wherein Y is C₁alkyl. Another embodimentprovides the compound of Formula (V), or pharmaceutically acceptablesalt thereof, wherein Y is C₂alkyl.

Another embodiment provides the compound of Formula (V), orpharmaceutically acceptable salt thereof, wherein m is 0. Anotherembodiment provides the compound of Formula (V), or pharmaceuticallyacceptable salt thereof, wherein m is 1. Another embodiment provides thecompound of Formula (V), or pharmaceutically acceptable salt thereof,wherein m is 2.

Another embodiment provides the compound of Formula (V), orpharmaceutically acceptable salt thereof, wherein Z is halogen, —CN,alkyl, alkoxy, carbocyclyl, or heterocyclyl. Another embodiment providesthe compound of Formula (V), or pharmaceutically acceptable saltthereof, wherein Z is fluoro, chloro, methyl, methoxy, or morpholinyl.

One embodiment provides a compound of Formula (VI), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Z is N or C—H;R is alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, orcarbocyclylalkyl.

One embodiment provides a compound of Formula (VI) having the structureof Formula (VIa), or pharmaceutically acceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Z is N or C—H;R is alkyl, aryl, aralkyl, or carbocyclylalkyl.

Another embodiment provides the compound of Formula (VI), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (VI), or pharmaceuticallyacceptable salt thereof, wherein n is 1 and X is fluoro.

Another embodiment provides the compound of Formula (VI), orpharmaceutically acceptable salt thereof, wherein Z is N. Anotherembodiment provides the compound of Formula (VI), or pharmaceuticallyacceptable salt thereof, wherein Z is C—H.

Another embodiment provides the compound of Formula (VI), orpharmaceutically acceptable salt thereof, wherein R is aralkyl. Anotherembodiment provides the compound of Formula (VI), or pharmaceuticallyacceptable salt thereof, wherein the aralkyl is benzyl.

Another embodiment provides the compound of Formula (VI), orpharmaceutically acceptable salt thereof, wherein R is alkyl. Anotherembodiment provides the compound of Formula (VI), or pharmaceuticallyacceptable salt thereof, wherein the alkyl is methyl.

One embodiment provides a compound of Formula (VII), or pharmaceuticallyacceptable salt thereof,

wherein,A1, A2, and A3 are chosen from C—H, N or N—R, provided that at least oneof A1, A2, or A3 is C—H, and at least one of A1, A2, or A3 is N—R; andR is aryl, aralkyl, or carbocyclylalkyl.

Another embodiment provides the compound of Formula (VII), orpharmaceutically acceptable salt thereof, having a structure selectedfrom Formula (VIIa)-(VIId) as described below:

Another embodiment provides the compound of Formula (VII), orpharmaceutically acceptable salt thereof, wherein R is aralkyl. Anotherembodiment provides the compound of Formula (VII), or pharmaceuticallyacceptable salt thereof, wherein the aralkyl is benzyl.

One embodiment provides a compound of Formula (VIII), orpharmaceutically acceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is C₁-C₃alkyl; andZ is aralkyl.

Another embodiment provides the compound of Formula (VIII), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (VIII), or pharmaceuticallyacceptable salt thereof, wherein n is 1 and X is fluoro.

Another embodiment provides the compound of Formula (VIII), orpharmaceutically acceptable salt thereof, wherein Y is C₁alkyl. Anotherembodiment provides the compound of Formula (VIII), or pharmaceuticallyacceptable salt thereof, wherein Y is C₂alkyl.

Another embodiment provides the compound of Formula (VIII), orpharmaceutically acceptable salt thereof, wherein Z is benzyl.

One embodiment provides a compound of Formula (IX), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is C₁-C₃alkyl; andZ is aralkyl.

Another embodiment provides the compound of Formula (IX), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (IX), or pharmaceuticallyacceptable salt thereof, wherein n is 1 and X is fluoro.

Another embodiment provides the compound of Formula (IX), orpharmaceutically acceptable salt thereof, wherein Y is C₁alkyl. Anotherembodiment provides the compound of Formula (IX), or pharmaceuticallyacceptable salt thereof, wherein Y is C₂alkyl.

Another embodiment provides the compound of Formula (IX), orpharmaceutically acceptable salt thereof, wherein Z is benzyl.

One embodiment provides a compound of Formula (X), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;ring A, represented by

R¹ is chosen from:

andR¹ is alkyl, aryl, aralkyl, carbocyclyl, carbocyclylalkyl, —(C═O)aryl,or —(SO₂)aryl.

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein n is 0. Anotherembodiment provides the compound of Formula (X), or pharmaceuticallyacceptable salt thereof, wherein n is 1 and X is fluoro.

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein ring A is

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein ring A is

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein ring A is

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein ring A is

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein ring A is

Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein R¹ is alkyl. Anotherembodiment provides the compound of Formula (X), or pharmaceuticallyacceptable salt thereof, wherein R¹ is aryl. Another embodiment providesthe compound of Formula (X), or pharmaceutically acceptable saltthereof, wherein the aryl is phenyl optionally substituted with halogen.Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein R¹ is aralkyl. Anotherembodiment provides the compound of Formula (X), or pharmaceuticallyacceptable salt thereof, wherein the aralkyl is benzyl optionallysubstituted with halogen. Another embodiment provides the compound ofFormula (X), or pharmaceutically acceptable salt thereof, wherein R¹ iscarbocyclyl. Another embodiment provides the compound of Formula (X), orpharmaceutically acceptable salt thereof, wherein R¹ iscarbocyclylalkyl.

One embodiment provides a compound of Formula (XI), or pharmaceuticallyacceptable salt thereof,

wherein,X is halogen and n is 0 or 1;Y is a heterocyclylene-; andZ is aryl, carbocyclyl, or heterocyclyl.

Another embodiment provides the compound of Formula (XI), orpharmaceutically acceptable salt thereof, wherein Z is aryl. Anotherembodiment provides the compound of Formula (XI), or pharmaceuticallyacceptable salt thereof, wherein Y is chosen from

One embodiment provides a compound, or pharmaceutically acceptable saltthereof, chosen from:

-   2-[4-(methyl-pyridin-2-yl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-methyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-phenethyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-benzyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(benzyl-methyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-[3-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-benzyl-1H-indol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-[3-(benzyl-methyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-[3-fluoro-4-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-benzyl-1H-indazol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(2-benzyl-2H-indazol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[methyl(2-phenylethyl)amino]phenoxy}pyridino[3,4-d]pyrimidin-4-ol;-   2-[2-benzyl-2H-indazol-5-yloxy]pyridino[3,4-d]pyrimidin-4-ol;-   2-(1-benzyl-1H-indazol-5-yloxy)-pyridino[3,4-d]pyrimidin-4-ol;-   2-{4-[(4-methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[(3-methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[methyl-(4-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[methyl-(3-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(methyl-p-tolyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;    and-   2-[4-(methyl-m-tolyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol.

An additional embodiment provides a compound, or pharmaceuticallyacceptable salt thereof, chosen from:

-   2-(4-{methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(4-{[4-(4-amino-piperidin-1-yl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   N-[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-N-methyl-2-phenyl-acetamide;-   2-[4-(3-phenyl-piperidin-1-yl)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(2-phenyl-morpholin-4-yl)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[methyl-(5-morpholin-4-yl-pyridin-3-yl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-(4-{[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   3-(4-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-phenyl)-butyronitrile;-   2-(1-cyclopentyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-phenyl-2,3-dihydro-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-phenyl-1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[(4-isopropyl-3-morpholin-4-yl-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-(4-{[4-(1-methoxy-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-(4-{[4-(2-amino-1-methyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[(4-{2-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-ethyl}-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-(4-{[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   3-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-benzonitrile;-   2-(4-{methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[(4-cyclopropyl-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[methyl-(5-methylpyridin-2-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(dimethylamino)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   4-[3-[4-(4-hydroxypyrido[3,4-d]pyrimidin-2-yl)oxy-N-methylanilino]phenyl]-1-methylpiperazin-2-one;-   2-[4-[N-methyl-4-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[3-(dimethylamino)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-3-pyrrolidin-1-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-4-pyrrolidin-1-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[3-(4-aminopiperidin-1-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[methyl-[(1S)-1-phenylethyl]amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[methyl-[(1R)-1-phenylethyl]amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(3-fluoro-N,4-dimethylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(3-phenylpyrrolidin-1-yl)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N,4-dimethyl-3-morpholin-4-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-3-methylsulfonylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-4-methylsulfonylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[3-(3-aminopiperidin-1-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(4-ethyl-N-methyl-3-morpholin-4-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-ethyl-N-methyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[methyl-(2-morpholin-4-ylpyridin-4-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[2,3-dihydro-1H-inden-1-ylmethyl(methyl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(2-methylpropyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(2-hydroxypropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[3-[2-(dimethylamino)ethoxy]-4-ethyl-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-ethyl-3-(2-methoxyethoxy)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(1-methoxy-2-methylpropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(1-hydroxy-2-methylpropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-4-propylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-[1-(methylamino)propan-2-yl]anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(4-aminobutan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-[4-(methylamino)butan-2-yl]anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(2,2,2-trifluoroethoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(2-methylpropoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(2,2-dimethylpropoxy)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(cyclopropylmethyl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-[(2S)-butan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-[(2R)-butan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-ethylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   4-[4-(4-hydroxypyrido[3,4-d]pyrimidin-2-yl)oxy-N-methylanilino]benzonitrile;-   2-[4-[methyl-(2-methylindazol-5-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N,3,4-trimethylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(4-ethyl-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-4-propan-2-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-3-(trifluoromethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(trifluoromethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-3-(4-methyl-1,4-diazepan-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-3-[methyl-(1-methylpiperidin-4-yl)amino]anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N,3-dimethyl-5-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[1-(oxan-4-yl)indol-5-yl]oxypyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(4-tert-butyl-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-3-propan-2-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(4-chloro-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(3-chloro-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(3-fluoro-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[(5-ethylpyridin-2-yl)-methylamino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(3,6-dihydro-2H-pyran-4-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(oxan-4-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-[1-(2-methoxyethylamino)propan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[4-(cyclopropylmethoxy)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-(2-methoxyethyl)-4-propan-2-ylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-(1-phenylindol-5-yl)oxypyrido[3,4-d]pyrimidin-4-ol;-   2-(1-piperidin-4-ylindol-5-yl)oxypyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N,4-dimethyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(2,2,2-trifluoroethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-[1-(trifluoromethyl)cyclopropyl]anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(1,1,1-trifluoropropan-2-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[methyl-(6-propan-2-ylpyridin-3-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-methyl-4-(trifluoromethoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-methyl-4-propan-2-yloxyanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-[N-(oxolan-3-yl)-4-propan-2-ylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-[4-(N-cyclobutyl-4-propan-2-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol;-   2-{4-[(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol;-   2-(4-{[4-(3-dimethylamino-1-methyl-propyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol;-   (3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-[4-(4-methyl-pyrido;    [3,4-d]pyrimidin-2-yloxy)-phenyl]-amine;-   2-(4-(ethyl(4-isopropylphenyl)amino)phenoxy)pyrido[3,4-d]pyrimidin-4-ol;    and-   2-(4-((4-isopropylphenyl)(tetrahydro-2H-pyran-4-yl)amino)phenoxy)pyrido[3,4-d]pyrimidin-4-ol.

In some embodiments, the compound disclosed herein has a structureprovided in Table 1.

TABLE 1 Ex Structure Name 1

2-[4-(methyl-pyridin-2-yl-amino)- phenoxy]-pyrido[3,4-d]pyrimidin-4-ol 2

2-(1-methyl-1H-indol-5-yloxy)-pyrido[3,4- d]pyrimidin-4-ol 3

2-(1-phenethyl-1H-indol-5-yloxy)- pyrido[3,4-d]pyrimidin-4-ol 4

2-(1-benzyl-1H-indol-5-yloxy)-pyrido[3,4- d]pyrimidin-4-ol 5

2-[4-(methyl-phenyl-amino)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 6

2-[4-(benzyl-methyl-amino)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 7

2-[3-(methyl-phenyl-amino)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 8

2-(1-benzyl-1H-indol-6-yloxy)-pyrido[3,4- d]pyrimidin-4-ol 9

2-[3-(benzyl-methyl-amino)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 10

2-[3-fluoro-4-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol 11

2-(1-benzyl-1H-indazol-6-yloxy)- pyrido[3,4-d]pyrimidin-4-ol 12

2-(2-benzyl-2H-indazol-6-yloxy)- pyrido[3,4-d]pyrimidin-4-ol 13

2-{4-[methyl(2- phenylethyl)amino]phenoxy}pyridino[3,4- d]pyrimidin-4-ol14

2-[2-benzyl-2H-indazol-5- yloxy]pyridino[3,4-d]pyrimidin-4-ol 15

2-(1-benzyl-1H-indazol-5-yloxy)- pyridino[3,4-d]pyrimidin-4-ol 16

2-{4-[(4-methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol 17

2-{4-[(3-methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol 18

2-{4-[methyl-(4-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin- 4-ol 19

2-{4-[methyl-(3-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin- 4-ol 20

2-[4-(methyl-p-tolyl-amino)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 21

2-[4-(methyl-m-tolyl-amino)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 22

2-(4-{methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amino}-phenoxy)-pyrido[3,4-d] pyrimidin-4-ol 23

2-(4-{[4-(4-amino-piperidin-1-yl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4- d]pyrimidin-4-ol 24

N-[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-N-methyl-2-phenyl- acetamide 25

2-[4-(3-phenyl-piperidin-1-yl)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 26

2-[4-(2-phenyl-morpholin-4-yl)-phenoxy]- pyrido[3,4-d]pyrimidin-4-ol 27

2-{4-[methyl-(5-morpholin-4-yl-pyridin-3-yl)-amino]-phenoxy}-pyrido[3,4- d]pyrimidin-4-ol 28

2-{4-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amino]-phenoxy}- pyrido[3,4-d]pyrimidin-4-ol 29

2-(4-{[4-(2-methoxy-1-methyl-ethyl)- phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol 30

3-(4-{[4-(4-hydroxy-pyrido[3,4- d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-phenyl)-butyronitrile 31

2-(1-cyclopentyl-1H-indol-5-yloxy)- pyrido[3,4-d]pyrimidin-4-ol 32

2-(1-phenyl-2,3-dihydro-1H-indol-5-yloxy)- pyrido[3,4-d]pyrimidin-4-ol33

2-(1-phenyl-1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol 34

2-{4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin- 4-ol 35

2-{4-[(4-isopropyl-3-morpholin-4-yl- phenyl)-methyl-amino]-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol 36

2-(4-{[4-(1-methoxy-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin- 4-ol 37

2-(4-{[4-(2-amino-1-methyl-ethyl)-phenyl] -methyl-amino}-phenoxy)-pyrido[3,4- d]pyrimidin-4-ol 38

2-{4-[(4-{2-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-ethyl}-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin- 4-ol 39

2-(4-{[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4- d]pyrimidin-4-ol 40

3-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-benzonitrile 41

2-(4-{methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amino}-phenoxy)- pyrido[3,4-d]pyrimidin-4-ol 42

2-{4-[(4-cyclopropyl-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin- 4-ol 43

2-[4-[methyl-(5-methylpyridin-2-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 44

2-[4-[4-(dimethylamino)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 45

4-[3-[4-(4-hydroxypyrido[3,4-d]pyrimidin-2-yl)oxy-N-methylanilino]phenyl]-1- methylpiperazin-2-one 46

2-[4-[N-methyl-4-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 47

2-[4-[3-(dimethylamino)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 48

2-[4-(N-methyl-3-pyrrolidin-1- ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 49

2-[4-(N-methyl-4-pyrrolidin-1- ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 50

2-[4-[3-(4-aminopiperidin-1-yl)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 51

2-[4-[methyl-[(1S)-1- phenylethyl]amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 52

2-[4-[methyl-[(1R)-1- phenylethyl]amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 53

2-[4-(3-fluoro-N,4- dimethylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol54

2-[4-(3-phenylpyrrolidin-1- yl)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 55

2-[4-(N,4-dimethyl-3-morpholin-4-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 56

2-[4-(N-methyl-3- methylsulfonylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 57

2-[4-(N-methyl-4- methylsulfonylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 58

2-[4-[3-(3-aminopiperidin-1-yl)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 59

2-[4-(4-ethyl-N-methyl-3-morpholin-4-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 60

2-[4-[4-ethyl-N-methyl-3-(4- methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 61

2-[4-[methyl-(2-morpholin-4-ylpyridin-4-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 62

2-[4-[2,3-dihydro-1H-inden-1- ylmethyl(methyl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 63

2-[4-[N-methyl-4-(2- methylpropyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 64

2-[4-[4-(2-hydroxypropan-2-yl)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 65

2-[4-[3-[2-(dimethylamino)ethoxy]-4-ethyl-N-methylanilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 66

2-[4-[4-ethyl-3-(2-methoxyethoxy)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 67

2-[4-[4-(1-methoxy-2-methylpropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 68

2-[4-[4-(1-hydroxy-2-methylpropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 69

2-[4-(N-methyl-4- propylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 70

2-[4-[N-methyl-4-[1-(methylamino)propan-2-yl]anilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 71

2-[4-[4-(4-aminobutan-2-yl)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 72

2-[4-[N-methyl-4-[4-(methylamino)butan- 2-yl]anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 73

2-[4-[N-methyl-4-(2,2,2- trifluoroethoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 74

2-[4-[N-methyl-4-(2- methylpropoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 75

2-[4-[4-(2,2-dimethylpropoxy)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 76

2-[4-[4-(cyclopropylmethyl)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 77

2-[4-[4-[(2S)-butan-2-yl]-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 78

2-[4-[4-[(2R)-butan-2-yl]-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 79

2-[4-[N-methyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 80

2-[4-(N-ethylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 81

4-[4-(4-hydroxypyrido[3,4-d]pyrimidin-2-yl)oxy-N-methylanilino]benzonitrile 82

2-[4-[methyl-(2-methylindazol-5-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 83

2-[4-(N,3,4- trimethylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 84

2-[4-(4-ethyl-N- methylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 85

2-[4-(N-methyl-4-propan-2- ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 86

2-[4-[N-methyl-3- (trifluoromethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 87

2-[4-[N-methyl-4- (trifluoromethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 88

2-[4-[N-methyl-3-(4-methyl-1,4-diazepan-1-yl)anilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 89

2-[4-[N-methyl-3-[methyl-(1- methylpiperidin-4-yl)amino]anilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 90

2-[4-[N,3-dimethyl-5-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 91

2-[1-(oxan-4-yl)indol-5-yl]oxypyrido[3,4- d]pyrimidin-4-ol 92

2-[4-(4-tert-butyl-N- methylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol93

2-[4-(N-methyl-3-propan-2- ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 94

2-[4-(4-chloro-N- methylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 95

2-[4-(3-chloro-N- methylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 96

2-[4-(3-fluoro-N- methylanilino)phenoxy]pyrido[3,4- d]pyrimidin-4-ol 97

2-[4-[(5-ethylpyridin-2-yl)- methylamino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 98

2-[4-[4-(3,6-dihydro-2H-pyran-4-yl)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 99

2-[4-[N-methyl-4-(oxan-4- yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 100

2-[4-[4-[1-(2-methoxyethylamino)propan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4- d]pyrimidin-4-ol 101

2-[4-[4-(cyclopropylmethoxy)-N- methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 102

2-[4-[N-(2-methoxyethyl)-4-propan-2-ylanilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 103

2-(1-phenylindol-5-yl)oxypyrido[3,4- d]pyrimidin-4-ol 104

2-(1-piperidin-4-ylindol-5- yl)oxypyrido[3,4-d]pyrimidin-4-ol 105

2-[4-[N,4-dimethyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 106

2-[4-[N-methyl-4-(2,2,2- trifluoroethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 107

2-[4-[N-methyl-4-[1- (trifluoromethyl)cyclopropyl]anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 108

2-[4-[N-methyl-4-(1,1,1-trifluoropropan-2-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 109

2-[4-[methyl-(6-propan-2-ylpyridin-3-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 110

2-[4-[N-methyl-4- (trifluoromethoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-ol 111

2-[4-(N-methyl-4-propan-2- yloxyanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 112

2-[4-[N-(oxolan-3-yl)-4-propan-2-ylanilino]phenoxy]pyrido[3,4-d]pyrimidin- 4-ol 113

2-[4-(N-cyclobutyl-4-propan-2- ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol 114

2-{4-[(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amino]-phenoxy}-pyrido[3,4- d]pyrimidin-4-ol 115

2-(4-{[4-(3-dimethylamino-1-methyl-propyl)-phenyl]-methyl-amino}-phenoxy)- pyrido[3,4-d]pyrimidin-4-ol 116

(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-[4-(4-methyl-pyrido[3,4- d]pyrimidin-2-yloxy)-phenyl]-amine117

2-(4-(ethyl(4- isopropylphenyl)amino)phenoxy)pyrido[3,4-d]pyrimidin-4-ol 118

2-(4-((4-isopropylphenyl)(tetrahydro-2H-pyran-4-yl)amino)phenoxy)pyrido[3,4- d]pyrimidin-4-ol

In some embodiments, the compound disclosed herein has a structureprovided in Table 2.

TABLE 2

Preparation of the Substituted Pyrido[3,4-d]pyrimidin-4-one DerivativeCompounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, “SyntheticOrganic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler etal., “Organic Functional Group Preparations,” 2nd Ed., Academic Press,New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.March, “Advanced Organic Chemistry: Reactions, Mechanisms andStructure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted pyrido[3,4-d]pyrimidin-4-onederivative compounds described herein is P. H. Stahl & C. G. Wermuth“Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta,Zurich, 2002.

The substituted pyrido[3,4-d]pyrimidin-4-one derivative compounds areprepared by the general synthetic routes described below in Scheme 1.

Referring to Scheme 1, compound A is converted to compound B bycondensation with urea. The azaquinazolinedione compound B is convertedto compound C using an appropriate chlorinating agent, such as POCl₃.Compound C is selectively hydrolyzed to form compound D under a varietyof basic conditions, such as hydrolysis in a NaOH solution. Nucleophilicsubstitution of the chloride in compound D is carried out with analcohol, such as G-OH, under a variety of basic conditions to formcompound F. For example, compound D can be treated with the sodium saltof the alcohol E. Additionally, compound D can be heated with thealcohol or phenol G-OH in the presence of CuI and CsCO₃ in anappropriate solvent to form compound F.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Pharmaceutical Compositions

In certain embodiments, a substituted pyrido[3,4-d]pyrimidin-4-onederivative compound as described by Formula (I)-(XI) is administered asa pure chemical. In other embodiments, the substitutedpyrido[3,4-d]pyrimidin-4-one derivative compound as described by Formula(I)-(XI) is combined with a pharmaceutically suitable or acceptablecarrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice as described, for example, in Remington: TheScience and Practice of Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co.,Easton, Pa. (2005)), the disclosure of which is hereby incorporatedherein by reference, in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted pyrido[3,4-d]pyrimidin-4-one derivativecompound, or a stereoisomer, pharmaceutically acceptable salt, hydrate,solvate, or N-oxide thereof, together with one or more pharmaceuticallyacceptable carriers. The carrier(s) (or excipient(s)) is acceptable orsuitable if the carrier is compatible with the other ingredients of thecomposition and not deleterious to the recipient (i.e., the subject) ofthe composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I) or apharmaceutically acceptable salt thereof. One embodiment provides apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (II) or a pharmaceutically acceptablesalt thereof. One embodiment provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound ofFormula (III) or a pharmaceutically acceptable salt thereof. Oneembodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (IV) or apharmaceutically acceptable salt thereof. One embodiment provides apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (V) or a pharmaceutically acceptablesalt thereof. One embodiment provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound ofFormula (VI) or a pharmaceutically acceptable salt thereof. Oneembodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (VII) or apharmaceutically acceptable salt thereof. One embodiment provides apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (VIII) or a pharmaceuticallyacceptable salt thereof. One embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (IX) or a pharmaceutically acceptable salt thereof.One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (X) or apharmaceutically acceptable salt thereof. One embodiment provides apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (XI) or a pharmaceutically acceptablesalt thereof.

In certain embodiments, the substituted pyrido[3,4-d]pyrimidin-4-onederivative compound as described by Formula (I)-(XI) is substantiallypure, in that it contains less than about 5%, or less than about 1%, orless than about 0.1%, of other organic small molecules, such ascontaminating intermediates or by-products that are created, forexample, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substitutedpyrido[3,4-d]pyrimidin-4-one derivative compound as described herein maydiffer, depending upon the patient's (e.g., human) condition, that is,stage of the disease, general health status, age, and other factors thata person skilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses can typically range from about 1.0 mg to about 1000 mg, oneto four times, or more, per day.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which can covalentlymodify histones at various sites.

Proteins can be post-translationally modified by methylation on aminogroups of lysines and guanidino groups of arginines or carboxymethylatedon aspartate, glutamate, or on the C-terminus of the protein.Post-translational protein methylation has been implicated in a varietyof cellular processes such as RNA processing, receptor mediatedsignaling, and cellular differentiation. Post-translational proteinmethylation is widely known to occur on histones, such reactions knownto be catalyzed by histone methyltransferases, which transfer methylgroups from S-adenyosyl methionine (SAM) to histones. Histonemethylation is known to participate in a diverse range of biologicalprocesses including heterochromatin formation, X-chromosomeinactivation, and transcriptional regulation (Lachner et al., (2003) J.Cell Sci. 116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet.Dev. 15:163-176).

Unlike acetylation, which generally correlates with transcriptionalactivation, whether histone methylation leads to transcriptionactivation or repression depends on the particular site of methylationand the degree of methylation (e.g., whether a particular histone lysineresidue is mono-, di-, or tri-methylated). However, generally,methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, whilemethylation on H3K4, H3K36, and H3K79 is generally associated withactive gene expression. In addition, tri- and di-methylation of H3K4generally marks the transcriptional start sites of actively transcribedgenes, whereas mono-methylation of H3K4 is associated with enhancersequences.

A “demethylase” or “protein demethylase,” as referred to herein, refersto an enzyme that removes at least one methyl group from an amino acidside chain. Some demethylases act on histones, e.g., act as a histone H3or H4 demethylase. For example, an H3 demethylase may demethylate one ormore of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4demethylase may demethylate histone H4K20. Demethylases are known whichcan demethylate either a mono-, di- and/or a tri-methylated substrate.Further, histone demethylases can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate and/oran oligonucleosome substrate, peptide substrate and/or chromatin (e.g.,in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 orH3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC)domain containing histone demethylases were predicted, and confirmedwhen a H3K36 demethylase was found using a formaldehyde release assay,which was named JmjC domain containing histone demethylase 1(JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified andthey can be phylogenetically clustered into seven subfamilies: JHDM1,JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 family of proteins are a family of histone-demethylases knownto demethylate tri- and di-methylated H3-K9, and were the firstidentified histone tri-methyl demethylases. In particular, ectopicexpression of JMJD2 family members was found to dramatically decreaselevels of tri- and di-methylated H3-K9, while increasing levels ofmono-methylated H3-K9, which delocalized Heterochromatin Protein 1 (HP1)and reduced overall levels of heterochromatin in vivo. Members of theJMJD2 subfamily of jumonji proteins include JMJD2C and its homologuesJMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found inthe JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD andTdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylatetri-methylated H3K9 and H3K36. Histone demethylation by JMJD2C occursvia a hydroxylation reaction dependent on iron and α-ketoglutarate,wherein oxidative decarboxylation of α-ketoglutarate by JMJD2C producescarbon dioxide, succinate, and ferryl and ferryl subsequentlyhydroxylates a methyl group of lysine H3K9, releasing formaldehyde.JMJD2C is known to modulate regulation of adipogenesis by the nuclearreceptor PPARγ and is known to be involved in regulation of self-renewalin embryonic stem cells.

JARID Family

As used herein, a “JARID protein” includes proteins in the JARID1subfamily (e.g., JARID1A, JARID1B, JARID1C and JARID1D proteins) and theJARID2 subfamily, as well as homologues thereof. A further descriptionand listing of JARID proteins can be found in Klose et al. (2006) NatureReviews/Genetics 7:715-727. The JARID1 family contains several conserveddomains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was initially found as a bindingpartner of retinoblastoma (Rb) protein. JARID1A was subsequently foundto function as a demethylase of tri- and di-methylated H3K4, and hasbeen found to promote cell growth, while inhibiting senescence anddifferentiation. For instance, abrogation of JARID1A from mouse cellsinhibits cell growth, induces senescence and differentiation, and causesloss of pluripotency of embryonic stem cells in vitro. JARID1A has beenfound to be overexpressed in gastric cancer and the loss of JARID1A hasbeen found to reduce tumorigenesis in a mouse cancer model.Additionally, studies have demonstrated that loss of the retinoblastomebinding protein 2 (RBP2) histone demethylase suppresses tumorigenesis inmice lacking Rb1 or Men1 (Lin et al. Proc. Natl. Acad. Sci. USA, Aug.16, 2011, 108(33),13379-86; doi: 10.1073/pnas.1110104108) and lead tothe conclusion that RBP2-inhibitory drugs would have anti-canceractivity.

JARID1B, also referred to as KDM5B and PLU1, was originally found inexperiments to discover genes regulated by the HER2 tyrosine kinase.JARID1B has consistently been found to be expressed in breast cancercell lines, although restriction of JARID1B has been found in normaladult tissues, with the exception of the testis. In addition, 90% ofinvasive ductal carcinomas have been found to express JARID1B. Inaddition, JARID1B has been found to be up-regulated in prostate cancers,while having more limited expression in benign prostate, and has alsobeen found to be up-regulated in bladder cancer and lung cancer (bothSCLC and NSCLC). JARID1B has also been found to repress tumor suppressorgenes such as BRCA1, CAV1 and 14-3-3σ, and knockdown of JARID1B wasfound to increase the levels of tri-methylated H3K4 at these genes.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (I) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (II) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (III) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (IV) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (V) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (VI) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (VII) or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (VIII) or a pharmaceuticallyacceptable salt thereof. In an additional embodiment is a method forinhibiting a histone-demethylase enzyme comprising contacting a histonedemethylase enzyme with a compound of Formula (IX) or a pharmaceuticallyacceptable salt thereof. In an additional embodiment is a method forinhibiting a histone-demethylase enzyme comprising contacting a histonedemethylase enzyme with a compound of Formula (X) or a pharmaceuticallyacceptable salt thereof. In an additional embodiment is a method forinhibiting a histone-demethylase enzyme comprising contacting a histonedemethylase enzyme with a compound of Formula (XI) or a pharmaceuticallyacceptable salt thereof.

In an additional embodiment is the method for inhibiting ahistone-demethylase enzyme, wherein the histone-demethylase enzymecomprises a jumonji domain. In an additional embodiment is the methodfor inhibiting a histone-demethylase enzyme, wherein thehistone-demethylase enzyme is JMJD2C.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, in particular embodiments, the invention provides a methodof treating a disease regulated by histone methylation and/ordemethylation in a subject in need thereof by modulating the activity ofa demethylase comprising a jumonji domain (e.g., a histone demethylasesuch as a JMJD2C protein).

In an additional embodiment is a method for treating cancer in subjectin need thereof comprising administering a composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof.In an additional embodiment is a method for treating cancer in subjectin need thereof comprising administering a composition comprising acompound of Formula (II), or a pharmaceutically acceptable salt thereof.In an additional embodiment is a method for treating cancer in subjectin need thereof comprising administering a composition comprising acompound of Formula (III), or a pharmaceutically acceptable saltthereof. In an additional embodiment is a method for treating cancer insubject in need thereof comprising administering a compositioncomprising a compound of Formula (IV), or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for treatingcancer in subject in need thereof comprising administering a compositioncomprising a compound of Formula (V), or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for treatingcancer in subject in need thereof comprising administering a compositioncomprising a compound of Formula (VI), or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for treatingcancer in subject in need thereof comprising administering a compositioncomprising a compound of Formula (VII), or a pharmaceutically acceptablesalt thereof. In an additional embodiment is a method for treatingcancer in subject in need thereof comprising administering a compositioncomprising a compound of Formula (VIII), or a pharmaceuticallyacceptable salt thereof. In an additional embodiment is a method fortreating cancer in subject in need thereof comprising administering acomposition comprising a compound of Formula (IX), or a pharmaceuticallyacceptable salt thereof. In an additional embodiment is a method fortreating cancer in subject in need thereof comprising administering acomposition comprising a compound of Formula (X), or a pharmaceuticallyacceptable salt thereof. In an additional embodiment is a method fortreating cancer in subject in need thereof comprising administering acomposition comprising a compound of Formula (XI), or a pharmaceuticallyacceptable salt thereof.

In a further embodiment is the method for treating cancer in a subjectwherein the cancer is selected from prostate cancer, breast cancer,bladder cancer, lung cancer or melanoma.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compoundselected from any one of Formula (I)-(XI), or a pharmaceuticallyacceptable salt thereof, wherein the tumor is characterized by a loss ofretinoblastoma gene (RB 1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compoundselected from any one of Formula (I)-(XI) or a pharmaceuticallyacceptable salt thereof, wherein the tumor is characterized by a loss ofmultiple endocrine neoplasia type 1 gene (Men1) function.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Preparation I: 2-Chloropyrido[3,4-d]pyrimidin-4-ol

Step A: Pyrido[3,4-d]pyridine-2,4(1H,3H)-dione

To a solution of 3-aminopyridine-4-carboxamide (5 g, 36.5 mmol) in THF(100 mL) was added triphosgene (11.9 g, 40.1 mmol) and TEA (7.4 g, 73mmol). The reaction mixture was refluxed for 2 h. The solution wasconcentrated in vacuo and the residue was triturated in water. The solidwas filtered and washed with water and THF. The solid was dried toafford 4.1 g (70%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ11.62 (s, 1H), 11.58 (s, 1H), 8.66 (s, 1H), 8.40 (d, 1H, J=5.2 Hz), 7.80(d, 1H, J=5.2 Hz).

Step B: 2,4-Dichloropyrido[3,4-d]pyrimidine

To a mixture of pyrido[3,4-d]pyridine-2,4(1H,3H)-dione (2 g, 12.3 mmol)in toluene (50 mL) was added DIEA (3.15 g, 25 mmol) and POCl₃ (9.5 g,61.4 mmol). The reaction mixture was refluxed overnight. The solutionwas concentrated in vacuo and the residue was taken in ethyl acetate andwashed with aq. NaHCO₃ and brine. The organics were dried andconcentrated. The residue was purified by silica gel chromatography (25%EA:PE) to afford 1 g (41%) of the title compound. ¹H NMR (400 MHz,DMSO-d₆): δ 9.50 (s, 1H), 8.90 (d, 1H, J=5.2 Hz), 8.02 (d, 1H, J=5.2Hz).

Step C: 2-Chloropyrido[3,4-d]pyrimidin-4-ol

To a solution of 2,4-dichloropyrido[3,4-d]pyrimidine (1 g, 5 mmol) inTHF (20 mL) was added a solution of NaOH (0.5 g, 12.5 mmol) in water (20mL). The reaction mixture was stirred at r.t. for 2 h. The solution wasadjusted to pH=2 using 5N HCl and the resulting precipitate was filteredand washed with water and THF, and dried to afford 0.8 g (88%) of thetitle compound.

¹H NMR (400 MHz, DMSO-d₆): δ 13.61 (s, 1H), 8.99 (s, 1H), 8.69 (d, 1H,J=5.2 Hz), 7.94 (d, 1H, J=5.2 Hz).

Preparation 1A: (4-Methoxy-phenyl)-pyridin-2-yl-amine

A mixture of 2-bromo-pyridine (2.00 g, 12.7 mmol), 4-methoxy-phenylamine(1.56 g, 12.7 mmol), Pd(OAc)₂ (290 mg, 1.27 mmol), BINAP (791 mg, 1.27mmol) and t-BuOK (2.84 g, 25.3 mmol) in toluene (30 mL) was stirredunder nitrogen atmosphere for 4 h at 125° C. The reaction mixture wasconcentrated. The residue was purified by silica gel chromatography(PE:EA 15:1) to give 1.78 g (70%) of the title compound. ¹H NMR (400MHz, CDCl₃): δ 3.81 (s, 3H), 6.47 (s, 1H), 6.67-6.68 (m, 2H), 6.88-6.92(m, 2H), 7.21-7.26 (m, 2H), 7.41-7.45 (m, 1H), 8.14 (d, J=4.0 Hz, 1H).[M+H] Calc'd for C₁₉H₁₅N₅O₂, 201. Found, 201.

Preparation 1B: (4-Methoxy-phenyl)-methyl-pyridin-2-yl-amine

To a solution of (4-methoxy-phenyl)-pyridin-2-yl-amine (1.78 g, 8.9mmol) in DMF (20 mL) was added t-BuOK (2.0 g, 17.8 mmol) at 0° C. Afterstirring for 30 min, MeI (2.53 g, 17.8 mmol) was added dropwise over 10min and the reaction mixture was stirred at rt overnight. The reactionmixture was diluted with water (100 mL), extracted with DCM (30 mL*3).The combined organic layers were washed with water (150 mL*3), brine(150 mL), dried over Na₂SO₄, and concentrated to give 1.47 g (77%) ofthe title product. ¹H NMR (400 MHz, CDCl₃): δ 3.42 (s, 3H), 3.83 (s,3H), 6.37 (d, J=8.8 Hz, 1H), 6.54-6.57 (m, 1H), 6.93-6.95 (m, 2H),7.16-7.19 (m, 2H), 7.26-7.28 (m, 1H), 8.19-8.21 (m, 1H). [M+H] Calc'dfor C₁₃H₁₄N₂O, 215. Found, 215.

Preparation 1C: 4-(Methyl-pyridin-2-yl-amino)-phenol

To a solution of (4-methoxy-phenyl)-methyl-pyridin-2-yl-amine (600 mg,2.8 mmol) in DCM (12 mL) was added dropwise BBr₃ (28 mL, 28 mmol, 1M inDCM) at 0° C. The reaction mixture was stirred for 30 min and carefullyquenched with MeOH at 0° C. The volatiles were concentrated in vacuo.The residue was dissolved in DCM (20 mL), washed with saturated NaHCO₃solution (50 mL) and brine (50 mL), dried over Na₂SO₄, and concentratedto give 450 mg (80%) of the title product. ¹H NMR (400 MHz, CDCl₃): δ3.41 (s, 3H), 6.41 (d, J=8.8 Hz, 1H), 6.56-6.59 (m, 1H), 6.85-6.87 (m,2H), 7.08-7.11 (m, 2H), 7.29-7.33 (m, 1H), 8.17-8.19 (m, 1H). [M+H]Calc'd for C₁₂H₁₂N₂O, 200. Found, 201.

Example 1:2-[4-(Methyl-pyridin-2-yl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

A mixture of 2-chloro-pyrido[3,4-d]pyrimidin-4-ol (408 mg, 2.25 mmol),4-(methyl-pyridin-2-yl-amino)-phenol (450 mg, 2.25 mmol), Cs₂CO₃ (734mg, 2.25 mmol), and CuI (428 mg, 2.25 mmol) in DMF (5 mL) was stirred at130° C. under nitrogen atmosphere overnight. The reaction mixture wasconcentrated. The residue was purified by HPLC to obtain 156 mg (20%) ofthe title product. ¹H NMR (400 MHz, DMSO-d₆): δ 3.43 (s, 3H), 6.63 (d,J=7.2 Hz, 1H), 6.70-6.73 (m, 2H), 7.38-7.40 (m, 4H), 7.48-7.52 (m, 1H),8.02-8.11 (m, 1H), 8.17 (d, J=4.0 Hz, 1H), 8.62-8.7 (m, 1H), 13.14 (s,1H). [M+H] Calc'd for C₁₉H₁₅N₅O₂, 346. Found, 346.

Preparation 2A: 5-Benzyloxy-1-methyl-1H-indole

To a solution of 5-benzyloxy-1H-indole (2.23 g, 10 mmol) in DMF (20 mL)at 0° C. was added NaH (480 mg, in mineral oil, 60%, 12 mmol) inportions and the mixture was stirred for 30 min. MeI was then added andthe mixture was stirred at rt overnight. The reaction mixture wasdiluted with water (100 mL) and extracted with DCM (30 mL*3). Organicswere dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel chromatography (PE:EA 50:1) to give 1.97 g (83%) of the titleproduct. ¹H NMR (400 MHz, CDCl₃): δ 3.77 (s, 3H), 5.11 (s, 2H), 6.39 (d,J=3.2 Hz, 1H), 6.97 (dd, J=2.4, 8.8 Hz, 1H), 7.01 (d, J=3.2 Hz, 1H),7.17 (d, J=2.0 Hz, 1H), 7.22 (J=10.8 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H),7.39 (t, J=7.2 Hz, 2H), 7.48 (d, J=7.2 Hz, 2H). [M+H] Calc'd forC₁₆H₁₅NO, 238. Found, 238.

Preparation 2B: 1-Methyl-1H-indol-5-ol

A mixture of 5-benzyloxy-1-methyl-1H-indole (1.97 g, 8.31 mmol) and Pd/C(0.5 g, 10% wet) in EtOH was stirred overnight under H₂ atmosphere. Thereaction mixture was filtered through a Celite pad. The filtrate wasconcentrated to give 1.2 g (98%) of the title product. ¹H NMR (400 MHz,CDCl₃): δ 3.75 (s, 3H), 6.35 (d, J=2.8 Hz, 1H), 6.80 (dd, J=2.4, 8.8 Hz,1H), 7.01-7.03 (m, 2H), 7.17 (d, J=8.8 Hz, 1H). [M+H] Calc'd for C₉H₉NO,148. Found, 148.

Example 2: 2-(1-Methyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 2.5% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-methyl-1H-indol-5-olaccording to the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ3.83 (s, 3H), 6.45 (d, J=2.8 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.40-7.43(m, 2H), 7.48 (d, J=8.8 Hz, 1H), 7.84 (d, J=4.8 Hz, 1H), 8.44 (d, J=4.4Hz, 1H), 8.59 (s, 1H). [M+H] Calc'd for C₁₆H₁₂N₄O₂, 293. Found, 293.

Preparation 3A: 5-Benzyloxy-1-phenethyl-1H-indole

A mixture of 5-benzyloxy-1H-indole (3.0 g, 13.5 mmol),(2-bromo-ethyl)-benzene (3.0 g, 16.1 mmol) and KOH (2.7 g, 40.4 mmol) inDMSO (25 mL) was stirred at 100° C. overnight. The reaction mixture wasdiluted with water (50 mL) and extracted with EA (20 mL*3). The organiclayers were combined, washed with water (30 mL*3), washed with brine,dried over Na₂SO₄, and concentrated. The residue was purified by silicagel chromatography (PE:EA 50:1) to give 1.9 g (43%) of the titleproduct. ¹H NMR (400 MHz, CDCl₃): δ 3.08 (t, J=7.2 Hz, 2H), 4.29 (t,J=7.2 Hz, 2H), 5.10 (s, 2H), 6.33 (d, J=2.8 Hz, 1H), 6.88 (d, J=2.8 Hz,1H), 6.94 (dd, J=2.8, 8.8 Hz, 1H), 7.07 (d, J=6.8 Hz, 2H), 7.16 (d,J=2.4 Hz, 1H), 7.21-7.26 (m, 4H), 7.31 (t, J=7.2 Hz, 1H), 7.38 (t, J=7.2Hz, 2H), 7.47 (d, J=7.6 Hz, 2H). [M+H] Calc'd for C₂₃H₂₁NO, 328. Found,328.

Preparation 3B: 1-Phenethyl-1H-indol-5-ol

A mixture of 5-benzyloxy-1-phenethyl-1H-indole (1.9 g, 5.8 mmol) andPd/C (0.5 g, 10% wet) in EtOH was stirred under H₂ atmosphere overnight.The reaction mixture was filtered through a Celite pad. The filtrate wasconcentrated to give 1.2 g (87%) of the title product. ¹H NMR (400 MHz,CDCl₃): δ 3.08 (t, J=7.2 Hz, 2H), 4.29 (t, J=7.2 Hz, 2H), 6.29 (d, J=2.8Hz, 1H), 6.79 (dd, J=2.4, 8.8 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 7.02 (d,J=2.4 Hz, 1H), 7.06-7.08 (m, 2H), 7.16-7.29 (m, 5H). [M+H] Calc'd forC₁₆H₁₅NO, 238. Found, 238.

Example 3: 2-(1-Phenethyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 6% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-phenethyl-1H-indol-5-olaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 3.10 (t, J=7.0 Hz, 2H), 4.44 (t, J=7.0 Hz, 2H), 6.43(s, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.21-7.26 (m, 5H), 7.39 (s, 1H), 7.44(s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.87 (t, J=2.0 Hz, 1H), 8.48 (d, J=4.8Hz, 1H), 8.63 (s, 1H). [M+H] Calc'd for C₂₃H₁₈N₄O₂, 383. Found, 383.

Preparation 4A: 1-Benzyl-5-methoxy-1H-indole

To a solution of 5-methoxy-1H-indole (1.50 g, 10 mmol) in DMF (20 mL) at0° C. was added NaH (480 mg, in mineral oil, 60%, 12 mmol) in portions,and the mixture was stirred for 30 min. BnBr (2.09 g, 12 mmol) was thenadded and the mixture was stirred at rt overnight. The reaction mixturewas diluted with water (100 mL) and extracted with DCM (30 mL*3).Organics were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (PE:EA 20:1) to give 2.40 g (99%)of the title product. [M+H] Calc'd for C₁₆H₁₅NO, 238. Found, 238.

Example 4B: 1-Benzyl-1H-indol-5-ol

To a solution of 1-benzyl-5-methoxy-1H-indole (2.40 g, 10 mmol) in DCM(20 mL) was added BBr₃ (40 mL, 1.0 M in DCM, 40 mmol) in portions at 0°C., and the mixture was stirred at rt for 2 h. The reaction mixture wasdiluted with water (30 mL), basified to pH 5 with sat. Na₂CO₃, andextracted with DCM (30 mL*3). Organics were dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(PE:EA 10:1) to give 1.20 g (53%) of the title product. [M+H] Calc'd forC₁₅H₁₃NO, 224. Found, 224.

Example 4: 2-(1-Benzyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 19% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-benzyl-1H-indol-5-olaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, DMSO-d₆): δ 5.45 (s, 2H), 6.53 (d, J=2.1 Hz, 1H), 7.04-7.08 (m,1H), 7.24-7.36 (m, 5H), 7.49-7.55 (m, 2H), 7.63 (d, J=1.5 Hz, 1H),7.85-7.89 (m, 1H), 8.15 (brs, 2H), 13.04 (s, 1H). [M+H] Calc'd forC₂₂H₁₆N₄O₂, 369. Found, 369.

Preparation 5A: 4-(Methyl-phenyl-amino)-phenol

To a suspension of 4-bromo-phenol (2.00 g, 12 mmol), methyl-phenyl-amine(1.48 g, 14 mmol), Pd₂(dba)₃ (267 mg, 0.29 mmol) and2-dicyclohexyphosphino-biphenyl (121 mg, 0.35 mmol) in toluene (40 mL)was added LiHMDS (25 mL, 1.0 M in THF, 25 mmol) in portions undernitrogen atmosphere. The reaction mixture was stirred at 65° C.overnight, acidified to pH 6 with 1N HCl, washed with brine (50 mL),dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel column (PE:EA 10:1) to give 2 g (87%) of the titleproduct. [M+H] Calc'd for C₁₃H₁₃NO, 200. Found, 200.

Example 5:2-[4-(Methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 18% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 4-(methyl-phenyl-amino)-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 3.30 (s, 3H), 6.97-7.08 (m, 5H), 7.23-7.25 (m, 2H),7.30-7.34 (m, 2H), 7.90-7.92 (m, 1H), 8.51-8.78 (m, 2H), 13.06 (s, 1H).[M+H] Calc'd for C₂₀H₁₆N₄O₂, 345. Found, 345.

Preparation 6A: 4-(Benzyl-methyl-amino)-phenol

The title compound was prepared in 41% yield from 4-bromo-phenol andbenzyl-methyl-amine according to the procedure of Preparation 5A. [M+H]Calc'd for C₁₄H₁₅NO, 214. Found, 214.

Example 6:2-[4-(Benzyl-methyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 5% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 4-(benzyl-methyl-amino)-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, DMSO-d₆): δ 3.04 (s, 3H), 4.56 (s, 2H), 6.75-6.77 (m, 2H),7.09-7.12 (m, 2H), 7.20-7.36 (m, 5H), 7.91-7.95 (m, 1H), 8.47-8.96 (m,2H), 12.98 (s, 1H). [M+H] Calc'd for C₂₁H₁₈N₄O₂, 359. Found, 359.

Preparation 7A: 3-(Methyl-phenyl-amino)-phenol

The title compound was prepared in 78% yield from 3-bromo-phenol andmethyl-phenyl-amine according to the procedure of Preparation 5A. [M+H]Calc'd for C₁₃H₁₃NO, 200. Found, 200.

Example 7:2-[3-(Methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 26% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 3-(methyl-phenyl-amino)-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 3.31 (s, 3H), 6.79-6.86 (m, 3H), 7.05 (t, J=7.2 Hz,1H), 7.17-7.19 (m, 2H), 7.32-7.36 (m, 3H), 7.88-7.95 (m, 1H), 8.45-8.73(m, 2H), 13.03 (s, 1H). [M+H] Calc'd for C₂₀H₁₆N₄O₂, 345. Found, 345.

Example 8: 2-(1-Benzyl-1H-indol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 16% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-benzyl-1H-indol-6-olaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 5.41 (s, 2H), 6.55 (d, J=2.8 Hz, 1H), 6.98-7.01 (m,1H), 7.23-7.32 (m, 5H), 7.50-7.52 (m, 1H), 7.57-7.62 (m, 2H), 7.87-7.94(m, 1H), 8.52-8.63 (m, 2H), 13.07 (s, 1H). [M+H] Calc'd for C₂₂H₁₆N₄O₂,369. Found, 369.

Preparation 9A: 3-(Benzyl-methyl-amino)-phenol

The title compound was prepared in 24% yield from 3-bromo-phenol andbenzyl-methyl-amine according to the procedure of Preparation 5A. [M+H]Calc'd for C₁₄H₁₅NO, 214. Found, 214.

Example 9:2-[3-(Benzyl-methyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 19% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 3-(benzyl-methyl-amino)-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 3.03 (s, 3H), 4.59 (s, 2H), 6.55-6.57 (m, 1H),6.64-6.69 (m, 2H), 7.23-7.32 (m, 7H), 7.92-8.20 (br, 2H), 13.02 (s, 1H).[M+H] Calc'd for C₂₁H₁₈N₄O₂, 359. Found, 359.

Preparation 10A: 3-Fluoro-4-(methyl-phenyl-amino)-phenol

The title compound was prepared in 18% yield from4-bromo-3-fluoro-phenol and methyl-phenyl-amine according to theprocedure of Preparation 5A. [M+H] Calc'd for C₁₃H₁₂FNO, 218. Found,218.

Example 10:2-[3-Fluoro-4-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 4% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and3-fluoro-4-(methyl-phenyl-amino)-phenol according to the procedure forthe preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 3.32 (s, 3H),6.68-6.77 (m, 5H), 7.17-7.20 (m, 4H), 7.34-7.42 (m, 2H). [M+H] Calc'dfor C₂₀H₁₅FN₄O₂, 363. Found, 363.

Preparation 11A: 1-Benzyl-6-methoxy-1H-indazole

The title compound was prepared in 62% yield from 6-methoxy-1H-indazoleand bromomethyl-benzene according to the procedure of Preparation 4A. ¹HNMR (400 MHz, CDCl₃): δ 3.85 (s, 3H), 5.53 (s, 2H), 6.76-6.78 (m, 1H),6.98 (s, 1H), 7.26-7.37 (m, 5H), 7.47-7.49 (m, 1H), 7.78 (s, 1H). [M+H]Calc'd for C₁₅H₁₄N₂O, 239. Found, 239.

Preparation 11B: 1-Benzyl-1H-indazol-6-ol

The title compound was prepared in 69% yield from1-benzyl-6-methoxy-1H-indazole according to the procedure of Preparation4B. ¹H NMR (400 MHz, DMSO-d₆): δ 5.51 (s, 2H), 6.65-6.68 (m, 1H), 6.79(s, 1H), 7.15-7.32 (m, 5H), 7.54 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 9.63(s, 1H). [M+H] Calc'd for C₁₄H₁₂N₂O, 225. Found, 225.

Example 11: 2-(1-Benzyl-1H-indazol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 16% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-benzyl-1H-indazol-6-olaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, DMSO-d₆): δ 5.64 (s, 2H), 7.13-7.16 (m, 1H), 7.25-7.33 (m, 5H),7.79-7.91 (m, 3H), 8.17 (m, 1H), 8.44-8.78 (m, 2H), 13.20 (s, 1H). [M+H]Calc'd for C₂₁H₁₅N₅O₂, 370. Found, 370.

Preparation 12A: 2-Benzyl-6-methoxy-1H-indazole

The title compound was prepared in 31% yield from 6-methoxy-1H-indazoleand bromomethyl-benzene according to the procedure of Preparation 4A.[M+H] Calc'd for C₁₅H₁₄N₂O, 239. Found, 239.

Preparation 12B: 2-Benzyl-1H-indazol-6-ol

The title compound was prepared in 74% yield from2-benzyl-6-methoxy-1H-indazole according to the procedure of Preparation4B. [M+H] Calc'd for C₁₄H₁₂N₂O, 225. Found, 225.

Example 12: 2-(2-Benzyl-2H-indazol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 1% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 2-benzyl-1H-indazol-6-olaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, DMSO-d₆): δ 5.66 (s, 2H), 7.01-7.05 (m, 1H), 7.29-7.37 (m, 5H),7.52 (s, 1H), 7.79-7.88 (m, 2H), 8.49-8.65 (m, 3H), 13.11 (s, 1H). [M+H]Calc'd for C₂₁H₁₅N₅O₂, 370. Found, 370.

Preparation 13A: 4-[Methyl(2-phenylethyl)amino]phenol

To a solution of 4-bromophenol (2.0 g, 11.56 mmol) andmethyl(2-phenylethyl)amine (1.88 g, 13.9 mmol) in toluene (20 mL) wasadded Pd₂(dba)₃ (110 mg, 0.12 mmol) anddicyclohexyl(2-phenylphenyl)phosphine (98 mg, 0.28 mmol), then LiHMDS(25.4 mL, 25.4 mmol) was added under nitrogen. The mixture was stirredovernight at 65° C. under nitrogen. The reaction mixture was filteredand concentrated. The residue was purified by prep-HPLC to give the 1.52g (58%) of the title product. [M+H] Calc'd for C₁₅H₁₇NO, 228. Found,228.

Example 13:2-{4-[Methyl(2-phenylethyl)amino]phenoxy}pyridino[3,4-d]pyrimidin-4-ol

The title compound was prepared in 17% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[methyl(2-phenylethyl)amino]phenol according to the procedure for thepreparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 2.82 (t, J=7.6Hz, 2H), 2.90 (s, 3H), 3.56 (t, J=7.8 Hz, 2H), 6.76 (d, J=9.2 Hz, 2H),7.13 (d, J=8.8 Hz, 2H), 7.20-7.23 (m, 1H), 7.28-7.31 (m, 4H), 7.86 (d,J=4.8 Hz, 1H), 8.49 (d, J=4.8 Hz, 1H), 8.68 (s, 1H). [M+H] Calc'd forC₂₂H₂₀N₄O₂, 373. Found, 373.

Preparation 14A and 15A: 5-Methoxy-2-benzyl-2H-indazole and5-methoxy-1-benzyl-1H-indazole

To a solution of 5-methoxy-1H-indazole (1.0 g, 6.76 mmol) in DMF (10 mL)was added Cs₂CO₃ (2.2 g, 6.76 mmol) and BnBr (1.38 g, 8.1 mmol). Themixture was stirred at rt for 3 h, diluted with water (100 mL), andextracted with EA. Organics were washed with brine, dried over Na₂SO₄,and concentrated. The residue was purified by prep-HPLC to give 576 mgof the product 14A (54%) and 863 mg of the product 15A (36%). 14A: ¹HNMR (400 MHz, CDCl₃): δ 3.81 (s, 3H), 5.56 (s, 2H), 6.84 (d, J=2.4 Hz,1H), 6.99 (dd, J=2.0, 7.2 Hz, 1H), 7.25-7.28 (m, 2H), 7.31-7.37 (m, 3H),7.61 (d, J=9.6 Hz, 1H), 7.75 (s, 1H). 15A: ¹H NMR (400 MHz, CDCl₃): δ3.84 (s, 3H), 5.57 (s, 2H), 7.00 (dd, J=2.8, 6.4 Hz, 1H), 7.08 (d, J=2.0Hz, 1H), 7.17-7.19 (m, 1H), 7.21-7.29 (m, 5H), 7.94 (s, 1H).

Preparation 14B: 2-Benzyl-2H-indazol-5-ol

The title compound was prepared in 47% yield from5-methoxy-2-benzyl-2H-indazole according to the procedure of Preparation1C. [M+H] Calc'd for C₁₄H₁₂N₂O, 225. Found, 225.

Example 14: 2-[2-Benzyl-2H-indazol-5-yloxy]pyridino[3,4-d]pyrimidin-4-ol

The title compound was prepared in 16% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 2-benzyl-2H-indazol-5-olaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 5.66 (s, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.32-7.37 (m,5H), 7.59 (d, J=1.6 Hz, 1H), 7.66 (d, J=9.6 Hz, 1H), 7.84 (d, J=4.8 Hz,1H), 8.45 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 8.62 (s, 1H). [M+H] Calc'dfor C₂₁H₁₅N₅O₂, 370. Found, 370.

Preparation 15B: 1-Benzyl-1H-indazol-5-ol

The title compound was prepared in 75% yield from5-methoxy-1-benzyl-1H-indazole according to the procedure of Preparation1C. [M+H] Calc'd for C₁₄H₁₂N₂O, 225. Found, 225.

Example 15:2-(1-Benzyl-1H-indazol-5-yloxy)-pyridino[3,4-d]pyrimidin-4-ol

The title compound was prepared in 16% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-benzyl-1H-indazol-5-olaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, DMSO-d₆): δ 5.71 (s, 2H), 7.22-7.41 (m, 9H), 7.78-7.83 (m, 2H),7.16 (s, 1H), 13.12 (s, 1H). [M+H] Calc'd for C₂₁H₁₅N₅O₂, 370. Found,370.

Preparation 16A: 4-[(4-Methoxy-phenyl)-methyl-amino]-phenol

The title compound was prepared in 34% yield from 4-bromo-phenol andbenzyl-methyl-amine according to the Preparation 5A. [M+H] Calc'd forC₁₄H₁₅NO₂, 230. Found, 230.

Example 16:2-{4-[(4-Methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 15% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-benzyl-1H-indazol-5-olaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 3.26 (s, 3H), 3.73 (s, 3H), 6.76 (d, J=9.2 Hz, 2H),6.97 (d, J=9.2 Hz, 2H), 7.12-7.16 (m, 4H), 7.89 (s, 1H), 8.52 (s, 1H),8.75 (s, 1H), 13.02 (s, 1H). [M+H] Calc'd for C₂₁H₁₈N₄O₃, 375. Found,375.

Preparation 17A: 4-[(3-Methoxy-phenyl)-methyl-amino]-phenol

The title compound was prepared in 34% yield from 4-bromo-phenol andbenzyl-methyl-amine according to the procedure of Preparation 5A. [M+H]Calc'd for C₁₄H₁₅NO₂, 230. Found, 230.

Example 17:2-{4-[(3-Methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 5% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-benzyl-1H-indazol-5-olaccording to the procedure for preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 3.29 (s, 3H), 3.73 (s, 3H), 6.54-6.61 (m, 3H),7.08-7.27 (m, 5H), 7.89 (s, 1H), 8.52 (s, 1H), 8.71 (s, 1H), 13.08 (s,1H). [M+H] Calc'd for C₂₁H₁₈N₄O₃, 375. Found, 375.

Preparation 18A: Methyl-(4-morpholin-4-yl-phenyl)-amine

A solution of 4-morpholin-4-yl-phenylamine (4 g, 22.5 mmol) in HCOOH (40mL) was heated at 110° C. overnight. The solution was diluted with water(100 mL) and extracted with DCM (30 mL×3). Organics were washed with H₂Oand brine, dried over Na₂SO₄, and concentrated in vacuo. To the residuein THF (100 mL) at 0° C. was added a 2M LiAlH₄ solution (33 mL), and themixture was stirred at rt for 2 h. H₂O (3 mL) was added at 0° C.,followed by 10% NaOH solution (6 mL). The mixture was filtered and thefiltrate was extracted with DCM (50 mL×2). The extracts were washed withbrine, dried over Na₂SO₄, concentrated in vacuo. The residue waspurified by silica gel chromatography (PE:EA 2:1) to give 4 g (93%) ofthe title compound. [M+H] Calc'd for C₁₁H₁₆N₂O, 193. Found, 193.

Preparation 18B: 4-[Methyl-(4-morpholin-4-yl-phenyl)-amino]-phenol

The title compound was prepared in 34% yield from 4-bromo-phenol andmethyl-(4-morpholin-4-yl-phenyl)-amine according to the procedure ofPreparation 5A. [M+H] Calc'd for C₁₇H₂₀N₂O₂, 285. Found, 285.

Example 18:2-{4-[Methyl-(4-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 2% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[methyl-(4-morpholin-4-yl-phenyl)-amino]-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ3.05-3.10 (m, 4H), 3.19 (s, 3H), 3.73-3.78 (m, 4H), 6.75 (d, J=9.2 Hz,2H), 6.97 (d, J=9.2 Hz, 2H), 7.06-7.12 (m, 4H), 7.86 (d, J=5.2 Hz, 1H),8.49-8.53 (m, 1H), 8.69 (s, 1H), 13.03 (s, 1H). [M+H] Calc'd forC₂₄H₅₅N₅O₃, 430. Found, 430.

Preparation 19A: Methyl-(3-morpholin-4-yl-phenyl)-amine

The title compound was prepared in 90% yield from3-morpholin-4-yl-phenylamine according to the procedure of Preparation18. [M+H] Calc'd for C₁₁H₁₆N₂O, 193. Found, 193.

Preparation 19B: 4-[Methyl-(3-morpholin-4-yl-phenyl)-amino]-phenol

The title compound was prepared in 45% yield from 4-bromo-phenol andmethyl-(3-morpholin-4-yl-phenyl)-amine according to the procedure ofpreparation of 5A. [M+H] Calc'd for C₁₇H₂₀N₂O₂, 285. Found, 285.

Example 19:2-{4-[Methyl-(3-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 3% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[methyl-(3-morpholin-4-yl-phenyl)-amino]-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ3.06-3.09 (m, 4H), 3.29 (s, 3H), 3.71-3.73 (m, 4H), 6.53-6.55 (m, 1H),6.62-6.64 (m, 2H), 6.97-6.99 (m, 2H), 7.16-7.21 (m, 3H), 7.87 (d, J=5.2Hz, 1H), 8.51 (d, J=4.8 Hz, 1H), 8.69 (s, 1H), 13.03 (s, 1H). [M+H]Calc'd for C₂₄H₅₅N₅O₃, 430. Found, 430.

Preparation 20: 4-(Methyl-p-tolyl-amino)-phenol

The title compound was prepared in 53% yield from 4-bromo-phenol andmethyl-p-tolyl-amine according to the procedure of preparation 5A. [M+H]Calc'd for C₁₄H₁₅NO, 214. Found 214.

Example 20:2-[4-(Methyl-p-tolyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 18% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 4-(methyl-p-tolyl-amino)-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 2.33 (s, 3H), 3.26 (s, 3H), 6.90 (d, J=8.8 Hz, 2H),6.99 (d, J=9.6 Hz, 2H), 7.15-7.22 (m, 4H), 7.86 (d, J=5.2 Hz, 1H), 8.50(d, J=4.8 Hz, 1H), 8.69 (s, 1H), 13.07 (s, 1H). [M+H] Calc'd forC₂₁H₁₈N₄O₂, 359. Found, 359.

Preparation 21: 4-(Methyl-m-tolyl-amino)-phenol

The title compound was prepared in 53% yield from 4-bromo-phenol andmethyl-m-tolyl-amine according to the procedure of Preparation 5A. [M+H]Calc'd for C₁₄H₁₅NO, 214. Found 214.

Example 21:2-[4-(Methyl-m-tolyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 15% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 4-(methyl-m-tolyl-amino)-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 2.28 (s, 3H), 3.29 (s, 3H), 6.82-6.88 (m, 3H), 7.01 (d,J=8.8 Hz, 2H), 7.19-7.23 (m, 3H), 7.87 (d, J=4.8 Hz, 1H), 8.51 (d, J=4.8Hz, 1H), 8.71 (s, 1H). [M+H] Calc'd for C₂₁H₁₈N₄O₂, 359. Found, 359.

Preparation 22A: (3-chloro-phenyl)-(4-methoxy-phenyl)-methyl-amine

To a solution of (3-chloro-phenyl)-methyl-amine (10 g, 71 mmol) intoluene was added 1-bromo-4-methoxy-benzene (14.0 g, 74.5 mmol),biphenyl-2-yl-dicyclohexyl-phosphane (270 mg, 0.71 mmol), Pd₂(dba)₃ (650mg, 0.71 mmol), t-BuOK (12.0 g, 106.5 mmol) and the mixture was refluxedovernight under nitrogen atmosphere. The reaction mixture was cooled toRT and the solvent was concentrated. The residue was purified by silicagel chromatography (PE:EA, 50:1) to give 15 g (86%) of the titlecompound. [M+H] Calc'd for C₁₄H₁₄ClNO, 248. Found, 248.

Preparation 22B:(4-methoxy-phenyl)-methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine

To a solution of ((3-chloro-phenyl)-(4-methoxy-phenyl)-methyl-amine (2.0g, 8.1 mmol) in toluene was added 1-methyl-piperazine (0.97 g, 9.7mmol), biphenyl-2-yl-dicyclohexyl-phosphane (155 mg, 0.4 mmol),Pd₂(dba)₃ (450 mg, 0.48 mmol), t-BuOK (2.5 g, 22.3 mmol) and the mixturewas refluxed overnight under nitrogen atmosphere. The reaction mixturewas cooled to RT and the solvent was concentrated. The residue waspurified by silica gel chromatography (DCM:MeOH, 20:1) to give 1.1 g(48%) of the title compound. [M+H] Calc'd for C₁₉H₂₅N₃O, 312. Found,312.

Preparation 22C:4-{methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amino}-phenol

To a solution of(4-methoxy-phenyl)-methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine(1.0 g, 3.2 mmol) in DCM (10 mL) was added BBr₃ (20 mL, 1M) at −20° C.and the mixture was stirred at RT for 1 h. The mixture was then warmedto 0° C., quenched with MeOH and the PH of the solution was neutralizedwith aqueous NaHCO₃. The organic layer was washed brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography (DCM:MeOH, 10:1) to give 370 mg (39%) of the titlecompound. [M+H] Calc'd for C₁₈H₂₃N₃O, 298. Found, 298.

Example 22:2-(4-{methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

A mixture of 2-chloro-pyrido[3,4-d]pyrimidin-4-ol (200 mg, 1.1 mmol),4-{methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amino}-phenol (370 mg,1.24 mmol), Cs₂CO₃ (400 mg, 1.22 mmol), and CuI (230 mg, 1.22 mmol) inDMF (10 mL) was stirred overnight at 130° C. under nitrogen atmosphere.The reaction mixture was concentrated and the residue was purified byprep-HPLC to give 30 mg (6%) of the title product. ¹H NMR (400 MHz,DMSO-d₆): δ 2.24 (s, 3H), 2.47-2.49 (m, 4H), 3.10-3.12 (m, 4H), 3.26 (s,3H), 6.49 (d, J=10.0 Hz, 1H), 6.60 (d, J=9.2 Hz, 2H), 6.96-7.17 (m, 5H),7.84 (d, J=6.8 Hz, 1H), 8.46 (d, J=6.8 Hz, 1H), 8.67 (s, 1H). [M+H]Calc'd for C₂₅H₂₆N₆O₂, 443. Found, 443.

Preparation 23A:(1-{3-[(4-methoxy-phenyl)-methyl-amino]-phenyl}-piperidin-4-yl)-carbamicacid tert-butyl ester

To a solution of ((3-chloro-phenyl)-(4-methoxy-phenyl)-methyl-amine (3.0g, 12.1 mmol) in toluene was added piperidin-4-yl-carbamic acidtert-butyl ester (3.65 g, 18.2 mmol), S-Phos (250 mg, 0.61 mmol),Pd₂(dba)₃ (670 mg, 0.73 mmol), t-BuOK (2.74 g, 24.5 mmol) and themixture was stirred overnight at 95° C. under nitrogen atmosphere. Thereaction mixture was cooled to RT and the solvent was concentrated. Theresidue was purified by silica gel chromatography (DCM:MeOH, 10:1) togive 0.65 g (27%) of the title compound. [M+H] Calc'd for C₂₄H₃₃N₃O₃,412. Found, 412.

Preparation 23B:4-{[3-(4-amino-piperidin-1-yl)-phenyl]-methyl-amino}-phenol

To a solution of(1-{3-[(4-methoxy-phenyl)-methyl-amino]-phenyl}-piperidin-4-yl)-carbamicacid tert-butyl ester (650 mg, 1.58 mmol) in DCM (10 mL) was added BBr₃(10 mL, 1 M) at −20° C. and the mixture was stirred at RT for 1 h. Themixture was then warmed to 0° C., quenched with MeOH and the PH of thesolution was neutralized with aqueous NaHCO₃. The residue was purifiedby silica gel chromatography (DCM:MeOH, 10:1) to give 360 mg (77%) ofthe title compound. [M+H] Calc'd for C₁₈H₂₃N₃O, 298. Found, 298.

Preparation 23B:(1-{3-[(4-hydroxy-phenyl)-methyl-amino]-phenyl}-piperidin-4-yl)-carbamicacid tert-butyl ester

To a solution of compound4-{[3-(4-amino-piperidin-1-yl)-phenyl]-methyl-amino}-phenol (360 mg,1.21 mmol) in MeOH (5 mL) was added was added 1N NaOH (2.42 mL) and(Boc)₂O (287 mg, 1.32 mmol) and the mixture was stirred at RT for 2 h.The reaction mixture was diluted with water and extracted with DCM (3×).The organics were concentrated and the residue was purified by silicagel chromatography (PE:EA, 5:1) to give 400 mg (83%) of the titlecompound. [M+H] Calc'd for C₂₃H₃₁N₃O₃, 398. Found, 398.

Example 23:2-(4-{[4-(4-amino-piperidin-1-yl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

A mixture of 2-chloro-pyrido[3,4-d]pyrimidin-4-ol (150 mg, 0.83 mmol),(1-{3-[(4-hydroxy-phenyl)-methyl-amino]-phenyl}-piperidin-4-yl)-carbamicacid tert-butyl ester (400 mg, 1.24 mmol), Cs₂CO₃ (300 mg, 0.92 mmol),and CuI (175 mg, 0.92 mmol) in DMF (10 mL) was stirred overnight at 130°C. under nitrogen atmosphere. The reaction mixture was concentrated. Theresidue was purified by silica gel chromatography (DCM:MeOH, 10:1) togive 30 mg of boc protected product, which was subsequently taken in DCM(10 mL). TFA (2 mL) was added to the solution and the mixture wasstirred at RT for 1 h. The solvent was concentrated and the residue waspurified by preparative HPLC to give 10 mg (3%) of the title product.[M+H] Calc'd for C₂₅H₂₆N₆O₂, 443. Found, 443.

Preparation 24A: N-(4-methoxy-phenyl)-N-methyl-2-phenyl-acetamide

Phenyl-acetyl chloride (2.0 g, 1.31 mmol) was added at 0° C. to asolution of (4-methoxy-phenyl)-methyl-amine (1.5 g, 1.1 mmol) and TEA(2.2 g, 2.2 mmol) in DCM (20 mL). The mixture was stirred at RT for 2 hand quenched with NH₄Cl. The mixture was concentrated and the residuewas purified by silica gel chromatography (PE:EA, 5:1) to give 2.0 g(71%) of the title compound. [M+H] Calc'd for C₁₆H₁₇NO₂, 256. Found,256.

Preparation 24B: N-(4-hydroxy-phenyl)-N-methyl-2-phenyl-acetamide

To a solution of N-(4-methoxy-phenyl)-N-methyl-2-phenyl-acetamide (2.0g, 10 mmol) in DCM (20 mL) was added BBr₃ (40 mL, 1.0 M in DCM, 40 mmol)in portions at 0° C., and the mixture was stirred at RT for 2 h. Thereaction mixture was diluted with water (30 mL), basified to pH 5 withsat. Na₂CO₃ and extracted with DCM (30 mL*3). The combined organics weredried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (PE:EA, 2:1) to give 1.5 g (94%) of the titleproduct. [M+H] Calc'd for C₁₅H₁₅NO₂, 242. Found, 242.

Example 24:N-[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-N-methyl-2-phenyl-acetamide

The title compound was prepared in 28% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol andN-(4-hydroxy-phenyl)-N-methyl-2-phenyl-acetamide according to theprocedure for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ3.20 (s, 2H), 3.44 (s, 3H), 7.05-7.40 (m, 9H), 7.87 (d, J=6.8 Hz, 1H),8.50 (d, J=6.8 Hz, 1H), 8.67 (s, 1H), 13.07 (s, 1H). [M+H] Calc'd forC₂₂H₁₈N₄O₃, 387. Found, 387.

Preparation 25A: 1-(4-methoxy-phenyl)-3-phenyl-piperidine

To a solution of 1-bromo-4-methoxy-benzene (0.5 g, 2.9 mmol) in toluenewas added 3-phenyl-piperidine (0.5 g, 3.2 mmol), S-Phos (60 mg, 0.15mmol), Pd₂(dba)₃ (160 mg, 0.17 mmol), t-BuOK (0.81 g, 7.23 mmol) and themixture was stirred overnight at 95° C. under nitrogen atmosphere. Thereaction mixture was cooled to RT and the solvent was concentrated. Theresidue was purified by silica gel chromatography (PE:EA, 10:1) to give0.5 g (52%) of the title compound. [M+H] Calc'd for C₁₈H₂₁NO, 268.Found, 268.

Preparation 25B: 4-(3-phenyl-piperidin-1-yl)-phenol

The title compound was prepared in 53% yield from1-(4-methoxy-phenyl)-3-phenyl-piperidine according to the procedure ofPreparation 22C. [M+H] Calc'd for C₁₇H₁₉NO, 254. Found 254.

Example 25:2-[4-(3-phenyl-piperidin-1-yl)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 15% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-(3-phenyl-piperidin-1-yl)-phenol according to the procedure for thepreparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.62-1.94 (m,4H), 2.72-2.83 (m, 3H), 3.69-3.76 (m, 2H), 7.00 (d, J=12.0 Hz, 2H), 7.13(d, J=12.0 Hz, 2H), 7.19-7.35 (m, 5H), 7.84 (d, J=7.6 Hz, 1H), 8.47 (d,J=7.2 Hz, 1H), 8.65 (s, 1H). [M+H] Calc'd for C₂₄H₂₂N₄O₂, 399. Found,399.

Preparation 26A: 4-(4-benzyloxy-phenyl)-2-phenyl-morpholine

The title compound was prepared in 80% yield from 2-phenylmorpholine and1-(benzyloxy)-4-bromobenzene according to the procedure of Preparation25A. [M+H] Calc'd for C₂₃H₂₃NO₂, 346 Found, 346.

Preparation 26B: 4-(2-phenyl-morpholin-4-yl)-phenol

To a solution of 4-(4-benzyloxy-phenyl)-2-phenyl-morpholine (1.5 g, 3.9mmol) in MeOH (20 mL) was added Pd/C (0.15 g), and the mixture wasstirred overnight under H₂ atmosphere. The reaction mixture was filteredand the filtrate was concentrated to give 0.99 g (99%) of the titlecompound. [M+H] Calc'd for C₁₆H₁₇NO₂, 256. Found, 256.

Example 26:2-[4-(2-phenyl-morpholin-4-yl)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 32% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-(2-phenyl-morpholin-4-yl)-phenol according to the procedure for thepreparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 2.25-2.63 (m,1H), 2.79-2.87 (m, 1H), 3.27-3.86 (m, 3H), 4.09-4.14 (m, 1H), 4.62-4.66(m, 1H), 7.06 (d, J=12.8 Hz, 2H), 7.17 (d, J=12.4 Hz, 2H), 7.29-7.48 (m,5H), 7.84 (d, J=7.6 Hz, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.65 (s, 1H), 13.07(s, 1H). [M+H] Calc'd for C₂₃H₂₀N₄O₃, 401. Found, 401.

Preparation 27A: (5-bromo-pyridin-3-yl)-methyl-carbamic acid tert-butylester

A solution of (5-bromo-pyridin-3-yl)-carbamic acid tert-butyl ester (3.4g, 12.5 mmol) in THF (10 mL) was added to a solution of NaH (0.75 g,18.8 mmol, 60% in mineral oil) in THF (15 mL) and the mixture wasstirred at RT for 10 min. CH₃I (2.13 g, 15.0 mmol) was added and themixture was stirred at RT for 2 h. The reaction was quenched withaqueous NH₄Cl and extracted with EtOAc (3×). The organics were combined,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (PE:EA, 10:1) to give 2.7 g (76%) of the titlecompound. [M+H] Calc'd for C₁₁H₁₅BrN₂O₂, 287. Found, 287.

Preparation 27B: methyl-(5-morpholin-4-yl-pyridin-3-yl)-amine

To a solution of (5-bromo-pyridin-3-yl)-methyl-carbamic acid tert-butylester (200 mg, 0.7 mmol) in toluene was added morpholine (120 mg, 1.4mmol), BINAP (87 mg, 0.14 mmol), Pd(OAc)₂ (16 mg, 0.07 mmol), Cs₂CO₃(2.5 g, 2.1 mmol) and the mixture was refluxed overnight under N₂atmosphere. The solvent was concentrated and the residue was purified bysilica gel chromatography (PE:EA, 1:1) to give boc-protected product,which was dissolved in DCM (2 mL). TFA was added to the solution and themixture was stirred at RT for 1 h. The solution was concentrated to give100 mg (74%) of the title compound as the TFA salt. [M+H] Calc'd forC₁₀H₁₅N₃O, 194. Found, 194.

Preparation 27C: 4-[methyl-(5-morpholin-4-yl-pyridin-3-yl)-amino]-phenol

The title compound was prepared in 34% yield from 4-bromo-phenol andmethyl-(5-morpholin-4-yl-pyridin-3-yl)-amine according to the procedureof Preparation 5A. [M+H] Calc'd for C₁₆H₁₉N₃O₂, 286. Found, 286.

Example 27:2-{4-[methyl-(5-morpholin-4-yl-pyridin-3-yl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 10% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[methyl-(5-morpholin-4-yl-pyridin-3-yl)-amino]-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ3.12-3.13 (m, 4H), 3.20 (s, 3H), 3.71-3.73 (m, 4H), 6.90 (s, 1H),7.07-7.09 (m, 2H), 7.23-7.26 (m, 2H), 7.75 (s, 1H), 7.86-7.90 (m, 2H),8.49 (s, 1H), 8.67 (s, 1H). [M+H] Calc'd for C₂₃H₂₂N₆O₃, 431. Found,431.

Preparation 28A: 1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide

SOCl₂ (2 mL) was added to a solution of1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (0.6 g, 3.4 mmol) inDCM (10 mL) and the mixture was refluxed for 2 h. The solvent wasconcentrated and the residue was added to a mixture of(4-methoxy-phenyl)-methyl-amine (470 mg, 3.4 mmol) and TEA (2 mL) in DCM(10 mL). The reaction mixture was stirred at RT for 5 h and quenchedwith 1N HCl (10 mL). The organic layer was separated, washed with water,washed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (PE:EA, 4:1) to give 630 mg (63%)of the title compound. [M+H] Calc'd for C₁₉H₂₁NO₂, 296. Found, 296.

Preparation 28B:(4-methoxy-phenyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amine

To a solution of 1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (600 mg, 2.0 mmol) in THF (10 mL) wasadded BH₃ (8 mL, 1N in Me₂S). The mixture was stirred at 40° C. for 2 h,cooled to RT and quenched with MeOH. The solution was adjusted to PH=9with 1N NaOH and extracted with EA (3×). The organics were combined,washed with water, washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(PE:EA, 10:1) to give 300 mg (53%) of the title compound. [M+H] Calc'dfor C₁₉H₂₃NO, 282. Found, 282.

Preparation 28C:4-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amino]-phenol

The title compound was prepared in 82% yield from 4-bromo-phenol and(4-methoxy-phenyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amineaccording to the procedure of Preparation 5A. [M+H] Calc'd for C₁₈H₂₁NO,268. Found, 268.

Example 28:2-{4-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 20% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amino]-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 1.65-1.89 (m, 4H), 2.67-2.74 (m, 2H), 2.96 (s, 3H),3.29-3.56 (m, 3H), 6.78 (d, J=11.2 Hz, 2H), 7.07-7.22 (m, 6H), 7.86 (s,1H), 8.49 (s, 1H), 8.67 (s, 1H), 12.99 (s, 1H). [M+H] Calc'd forC₂₅H₂₄N₄O₂, 413. Found, 413.

Preparation 29A: 2-(4-bromo-phenyl)-propionic acid methyl ester

To a solution of (4-bromo-phenyl)-acetic acid methyl ester (1.0 g, 4.37mmol) in THF was added LDA (4.4 mL, 1N) at −78° C. under N₂ atmosphereand the mixture was stirred at this temperature for 10 min. CH₃I (0.74g, 5.2 mmol) was added and the mixture was stirred at RT for 1 h,quenched with aqueous NH₄Cl and extracted with EA (3×). The organicswere combined, washed with water, washed with brine, dried over Na₂SO₄and concentrated. The residue was purified by silica gel chromatography(PE:EA, 20:1) to give 0.6 g (57%) of the title compound. [M+H] Calc'dfor C₁₀H₁₁BrO₂, 242. Found, 242.

Preparation 29B:2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propionic acid methylester

To a solution of 2-(4-bromo-phenyl)-propionic acid methyl ester (0.6 g,2.47 mmol) in toluene was added (4-benzyloxy-phenyl)-methyl-amine (526mg, 2.47 mmol), X-Phos (140 mg, 0.29 mmol), Pd(OAc)₂ (33 mg, 0.15 mmol),Cs₂CO₃ (3.2 g, 9.8 mmol) and the mixture was refluxed overnight. Thesolvent was concentrated and the residue was purified by silica gelchromatography (PE:EA, 10:1) to give 0.7 g (76%) of the title compound.[M+H] Calc'd for C₂₄H₂₅NO₃, 376. Found, 376.

Preparation 29C:2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propan-1-ol

To a solution of2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propionic acid methylester (0.7 g, 1.87 mmol) in THF (15 mL) was added LAH (1.6 mL, 1N) at 0°C. under N₂ atmosphere and the mixture was stirred at this temperaturefor 2 h. The reaction was warmed to RT, quenched with water andextracted with EA (3×). The organics were combined, washed with brine,dried over Na₂SO₄ and concentrated to give 0.6 g (92%) of the titlecompound. [M+H] Calc'd for C₂₃H₂₅NO₂, 348. Found, 348.

Preparation 29D:(4-benzyloxy-phenyl)-[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amine

To a solution of2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propan-1-ol (1.5 g, 4.3mmol) in DMF (20 mL) was added NaH (0.32 g, 7.8 mmol, 60% in mineraloil) at 0° C. After stirring for 30 min, MeI (0.92 g, 6.5 mmol) wasadded dropwise over 10 min and the reaction mixture was stirred at RTfor 3 h. The reaction mixture was diluted with water (100 mL), extractedwith EA (10 mL*3). The combined organic were washed with water (150mL*3), brine (150 mL), dried over Na₂SO₄, and concentrated to give 1.47g (77%) of the title product. [M+H] Calc'd for C₂₄H₂₇NO₂, 362. Found,362.

Preparation 29E:4-{[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amino}-phenol

The title compound was prepared in 100% yield from(4-benzyloxy-phenyl)-[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amineaccording to the procedure of Preparation 26B. [M+H] Calc'd forC₁₇H₂₁NO₂, 272 Found, 272.

Example 29:2-(4-{[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 20% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-{[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amino}-phenol accordingto the procedure for the preparation of Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.17 (t, J=9.2 Hz, 3H), 2.91-2.95 (m, 1H), 3.20 (s, 3H),3.30 (s, 3H), 3.35-3.38 (m, 2H), 6.93 (d, J=12.0 Hz, 2H), 7.01 (m,J=11.2 Hz, 2H), 7.16-7.19 (m, 4H), 7.86 (d, J=6.4 Hz, 1H), 8.48 (d,J=6.4 Hz, 1H), 8.67 (s, 1H). [M+H] Calc'd for C₂₄H₂₄N₄O₃, 417. Found,417.

Preparation 30A: methanesulfonic acid2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl ester

To a solution of2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propan-1-ol (1.5 g,4.32 mmol) in DCM (20 mL) was added TEA (0.72 g, 6.5 mmol) and MsCl(0.65 g, 5.6 mmol) at 0° C. and the mixture was stirred at RT for 2 h.The reaction mixture was washed with aqueous NH₄Cl, washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (PE:EA, 3:1) to give 1.4 g (76%) of the titlecompound. [M+H] Calc'd for C₂₄H₂₇NO₄S, 426. Found, 426.

Preparation 30B:3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyronitrile

To a solution of methanesulfonic acid2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl ester (1.35 g,3.17 mmol) in DMSO (20 mL) was added KCN (0.4 g, 6.34 mmol) and18-crown-6 (0.84 g, 3.17 mmol), and the mixture was stirred overnight at65° C. The reaction mixture was cooled to RT, quenched with water andextracted with EA (3×). The combined organics were washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (PE:EA, 5:1) to give 0.56 g (50%) of the titlecompound. [M+H] Calc'd for C₂₄H₂₄N₂O, 357. Found, 357.

Preparation 30C:3-{4-[(4-hydroxy-phenyl)-methyl-amino]-phenyl}-butyronitrile

The title compound was prepared in 88% yield from3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyronitrile accordingto the procedure of Preparation 26B. [M+H] Calc'd for C₁₇H₁₈N₂O, 267Found, 267.

Example 30:3-(4-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-phenyl)-butyronitrile

The title compound was prepared in 17% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and3-{4-[(4-hydroxy-phenyl)-methyl-amino]-phenyl}-butyronitrile accordingto the procedure for the preparation of Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.28 (d, J=9.2 Hz, 3H), 2.77 (d, J=9.2 Hz, 2H), 3.05-3.09(m, 1H), 3.27 (s, 3H), 6.95-6.99 (m, 4H), 7.19-7.27 (m, 4H), 7.86 (d,J=6.8 Hz, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.70 (s, 1H). [M+H] Calc'd forC₂₄H₂₁N₅O₂, 412. Found, 412.

Preparation 31A: 1-cyclopentyl-5-methoxy-1H-indole

To a solution of 5-methoxy-1H-indole (1.5 g, 10 mmol) in DMF (20 mL) at0° C. was added NaH (480 mg, in mineral oil, 60%, 12 mmol) in portionsand the mixture was stirred for 30 min. Bromo-cyclopentane (2.3 g, 15mmol) was then added and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with water (100 mL) and extracted with DCM(30 mL*3). The organics were combined, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(PE:EA, 20:1) to give 450 mg (21%) of the title product. [M+H] Calc'dfor C₁₄H₁₇NO, 216. Found, 216.

Preparation 31B: 1-cyclopentyl-1H-indol-5-ol

The title compound was prepared in 21% yield from1-cyclopentyl-5-methoxy-1H-indole according to the procedure for thepreparation of Example 4B. [M+H] Calc'd for C₁₃H₁₅NO, 202. Found, 202.

Example 31:2-(1-cyclopentyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 3% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and 1-cyclopentyl-1H-indol-5-olaccording to the procedure for the preparation of Example 1. ¹H NMR (400MHz, DMSO-d₆): δ 1.72-1.76 (m, 2H), 1.87-1.91 (m, 4H), 2.15-2.21 (m,2H), 4.92 (t, J=6.4 Hz, 1H), 6.49 (d, J=3.2 Hz, 1H), 7.08 (dd, J=1.6,7.2 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.54-7.59 (m, 2H), 7.88 (s, 1H),8.51 (brs, 1H), 8.64 (brs, 1H). [M+H] Calc'd for C₂₀H₁₈N₄O₂, 347. Found,347.

Preparation 32A: 5-benzyloxy-1-phenyl-1H-indole

A mixture of iodobenzene (1.83 g, 8.97 mmol), 5-benzyloxy-1H-indole (2.0g, 8.97 mmol), CuI (171 mg, 0.90 mmol) and Cs₂CO₃ (5.8 g, 17.94 mmol) inDMF (17 mL) was heated overnight at 120° C. The reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified byflash chromatography (PE:EA, 15:1 to 10:1) to give 1.29 g (49%) of thetitle compound. [M+H] Calc'd for C₂₁H₁₇NO, 300. Found, 300.

Preparation 32B: 1-phenyl-1H-indol-5-ol

To a solution of 5-benzyloxy-1-phenyl-1H-indole (100 mg, 0.33 mmol) inEtOH (20 mL) was added Pd/C (20 mg) and the mixture was stirredovernight at RT under H₂ atmosphere. The reaction mixture was filteredon celite and concentrated to give 70 mg (100%) of the title crudeproduct. [M+H] Calc'd for C₁₄H₁₁NO, 210. Found, 210.

Preparation 32C: 1-phenyl-2,3-dihydro-1H-indol-5-ol

To a solution of 1-phenyl-1H-indol-5-ol (500 mg, 2.4 mmol) in AcOH (10mL) was added NaBH₃CN (1.2 g, 19.1 mmol) and the reaction mixture wasstirred overnight at RT. The reaction was diluted with water, basifiedto pH 8 with sat. Na₂CO₃ and extracted with EA (3×). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give 200 mg (40%) of the title crude product. [M+H]Calc'd for C₁₅H₁₅NO, 226. Found, 226.

Example 32:2-(1-phenyl-2,3-dihydro-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 16% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and1-phenyl-2,3-dihydro-1H-indol-5-ol according to the procedure for thepreparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 3.14 (t, J=8.0Hz, 2H), 4.00 (t, J=8.4 Hz, 2H), 6.97 (d, J=6.8 Hz, 2H), 7.11 (d, J=8.4Hz, 1H), 7.16 (s, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.35-7.39 (m, 2H), 7.87(d, J=4.8 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.70 (s, 1H), 13.04 (brs,1H). [M+H] Calc'd for C₂₁H₁₆N₄O₂, 357. Found, 357.

Preparation 33A:6-(tert-butyl-dimethyl-silanyloxy)-1,2,3,4-tetrahydro-quinoline

To a solution of 1,2,3,4-tetrahydro-quinolin-6-ol (1.0 g, 6.7 mmol) andimidazole (1.4 g, 20.1 mmol) in DCM (20 mL) was added TBSCl (1.7 g, 7.4mmol) at ice-bath temperature, and the reaction was stirred at RT for 3h. The reaction was diluted with water and extracted with EA (3×). Thecombined organics were washed with brine, dried over Na₂SO₄, filteredand concentrated. The residue was purified by silica gel chromatography(PE:EA, 20:1) to give 1.7 g (97%) of the title product.

Preparation 33B:6-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-1,2,3,4-tetrahydro-quinoline

To a suspension of6-(tert-butyl-dimethyl-silanyloxy)-1,2,3,4-tetrahydro-quinoline (100 mg,0.38 mmol), iodo-benzene (78 mg, 0.38 mmol), BINAP (24 mg, 0.038 mmol)and Cs₂CO₃ (248 mg, 0.76 mmol) in toluene (10 mL) was added Pd₂(dba)₃(18 mg, 0.019 mmol) under N₂ atmosphere. The reaction was stirred atreflux overnight, filtered and the filtrate was concentrated. Theresidue was purified by silica gel chromatography (PE) to give 100 mg(78%) of the title product. [M+H] Calc'd for C₂₁H₂₉NOSi, 340. Found,340.

Preparation 33C: 1-phenyl-1,2,3,4-tetrahydro-quinolin-6-ol

To a solution6-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-1,2,3,4-tetrahydro-quinoline(700 mg, 2.1 mmol) in THF (20 mL) was added TBAF (4.1 mL, 1.0 M in THF,4.1 mmol) at RT and the reaction was stirred at RT for 30 min. Thereaction was diluted with water, extracted with EA (3×). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(PE:EA, 6:1) to give 250 mg (54%) of the title product. [M+H] Calc'd forC₁₅H₁₅NO, 226. Found, 226.

Example 33:2-(1-phenyl-1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 26% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and1-phenyl-1,2,3,4-tetrahydro-quinolin-6-ol according to the procedure forthe preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.96-1.98 (m,2H), 2.80 (t, J=6.0 Hz, 2H), 3.57 (t, J=6.0 Hz, 2H), 6.61 (d, J=9.0 Hz,1H), 6.84 (d, J=8.4 Hz, 1H), 6.98 (s, 1H), 7.08-7.12 (m, 1H), 7.24 (d,J=7.8 Hz, 2H), 7.34-7.39 (m, 2H), 7.84 (d, J=2.7 Hz, 1H), 8.48 (brs,1H), 8.68 (brs, 1H). [M+H] Calc'd for C₂₂H₁₈N₄O₂, 371. Found, 371.

Preparation 34A: 2-chloro-5-isopropenyl-pyridine

To a suspension of 2-chloro-5-iodo-pyridine (100 mg, 0.42 mmol),2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (75 mg, 0.42mmol), S-Phos (17 mg, 0.042 mmol) and K₃PO₄ (178 mg, 0.84 mmol) intoluene (10 mL) was added Pd₂(dba)₃ (8 mg, 0.008 mmol) under N₂atmosphere. The reaction was stirred at reflux overnight, filtered andthe filtrate was concentrated. The residue was purified by silica gelchromatography (PE:EA, 50:1) to give 30 mg (47%) of the title product.[M+H] Calc'd for C₈H₈ClN, 154. Found, 154.

Preparation 34B:(5-isopropenyl-pyridin-2-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared in 77% yield from2-chloro-5-isopropenyl-pyridine and (4-methoxy-phenyl)-methyl-amineaccording to the procedure of Preparation 34A. [M+H] Calc'd forC₁₆H₁₈N₂O, 255. Found, 255.

Preparation 34C:(5-isopropyl-pyridin-2-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared in 99% yield from(5-isopropenyl-pyridin-2-yl)-(4-methoxy-phenyl)-methyl-amine accordingto the procedure of Preparation 32B. [M+H] Calc'd for C₁₆H₂₀N₂O, 257.Found, 257.

Preparation 34D: 4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenol

The title compound was prepared in 59% yield from(5-isopropyl-pyridin-2-yl)-(4-methoxy-phenyl)-methyl-amine according tothe procedure of Preparation 4B. [M+H] Calc'd for C₁₅H₁₈N₂O, 243. Found,243.

Example 34:2-{4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 28% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.16 (d, J=6.6 Hz, 6H), 2.77-2.82 (m, 1H), 3.38 (s, 3H), 6.62 (d, J=8.7Hz, 1H), 7.34 (s, 4H), 7.41 (dd, J=2.7, 9.0 Hz, 1H), 7.87 (d, J=5.1 Hz,1H), 8.04 (d, J=2.1 Hz, 1H), 8.51 (d, J=3.9 Hz, 1H), 8.72 (s, 1H), 13.12(s, 1H). [M+H] Calc'd for C₂₂H₂₁N₅O₂, 388. Found, 388.

Preparation 35A:(4-isopropyl-3-nitro-phenyl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared in 81% yield from(4-methoxy-phenyl)-methyl-amine and 4-bromo-1-isopropyl-2-nitro-benzeneaccording to the procedure of Preparation 27B. [M+H] Calc'd forC₁₇H₂₀N₂O₃, 301. Found, 301.

Preparation 35B:4-isopropyl-N1-(4-methoxy-phenyl)-N1-methyl-benzene-1,3-diamine

The title compound was prepared in 96% yield from(4-isopropyl-3-nitro-phenyl)-(4-methoxy-phenyl)-methyl-amine accordingto the procedure of Preparation 32B. [M+H] Calc'd for C₁₇H₂₂N₂O, 271.Found, 271.

Preparation 35C:(4-isopropyl-3-morpholin-4-yl-phenyl)-(4-methoxy-phenyl)-methyl-amine

To a suspension of4-isopropyl-N1-(4-methoxy-phenyl)-N1-methyl-benzene-1,3-diamine (2.0 g,7.4 mmol), K₂CO₃ (5.1 g, 37.1 mmol) and NaI (2.0 g) in DMF (100 mL) wasadded 1-chloro-2-(2-chloro-ethoxy)-ethane (1.1 g, 7.4 mmol) and thereaction was stirred overnight at RT. The reaction was diluted withwater and extracted with EA (3×). The combined organics were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (PE:EA, 20:1) to give 1.5 g (60%)of the title product. [M+H] Calc'd for C₂₁H₂₈N₂O₂, 341. Found, 341.

Preparation 35D:4-[(4-isopropyl-3-morpholin-4-yl-phenyl)-methyl-amino]-phenol

The title compound was prepared in 59% yield from(4-isopropyl-3-morpholin-4-yl-phenyl)-(4-methoxy-phenyl)-methyl-amineaccording to the procedure of Preparation 4B. [M+H] Calc'd forC₂₀H₂₆N₂O₂, 327. Found, 327.

Example 35:2-{4-[(4-isopropyl-3-morpholin-4-yl-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 23% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.17 (d, J=6.8 Hz, 6H), 2.78 (t, J=4.0 Hz, 4H), 3.28 (s, 3H), 3.34-3.41(m, 1H), 3.72 (t, J=4.0 Hz, 4H), 6.84-6.86 (m, 2H), 6.96 (d, J=8.0 Hz,2H), 7.18-7.25 (m, 3H), 7.88 (d, J=5.2 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H),8.70 (s, 1H), 13.06 (brs, 1H). [M+H] Calc'd for C₂₇H₂₉N₅O₃, 472. Found,472.

Preparation 36A: 1-[4-(4-benzyloxy-phenylamino)-phenyl]-ethanone

A mixture of 1-(4-bromo-phenyl)-ethanone (10 g, 0.05 mol),4-benzyloxy-phenylamine (12 g, 0.06 mol), X-Phos (1.2 g, 2.5 mmol),Pd₂(dba)₃ (1.16 g, 1.26 mmol) and K₃PO₄ (16 g, 0.075 mol) in toluene(200 mL) was refluxed overnight under N₂ atmosphere. The reactionmixture was filtered and the filtrate was concentrated. The residue waspurified by silica gel chromatography (PE:EA, 5:1) to give 11.7 g of thetitle product. [M+H] Calc'd for C₂₁H₁₉NO₂, 318. Found, 318.

Preparation 36B:1-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-ethanone

The title compound was prepared in 68% yield from1-[4-(4-benzyloxy-phenylamino)-phenyl]-ethanone according to theprocedure of Preparation 27A. [M+H] Calc'd for C₂₂H₂₁NO₂, 332 Found,332.

Preparation 36C:1-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-ethanol

The title compound was prepared in 99% yield from1-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-ethanone according tothe procedure of Preparation 29C. [M+H] Calc'd for C₂₂H₂₃NO₂, 334 Found,334.

Preparation 36D:(4-benzyloxy-phenyl)-[4-(1-methoxy-ethyl)-phenyl]-methyl-amine

The title compound was prepared in 45% yield from1-[4-(4-benzyloxy-phenylamino)-phenyl]-ethanone according to theprocedure of Preparation 29D. [M+H] Calc'd for C₂₃H₂₅NO₂, 348 Found,348.

Preparation 36E: 4-{[4-(1-methoxy-ethyl)-phenyl]-methyl-amino}-phenol

To a solution of(4-benzyloxy-phenyl)-[4-(1-methoxy-ethyl)-phenyl]-methyl-amine (0.947 g,2.73 mmol) in THF (20 mL) was added Pd/C (0.10 g) and the mixture wasstirred overnight under H₂ atmosphere. The reaction mixture was filteredon celite and the filtrate was concentrated to give 0.34 g (50%) of thetitle compound. [M+H] Calc'd for C₁₆H₁₉NO₂, 258. Found, 258.

Example 36:2-(4-{[4-(1-methoxy-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 23% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-{[4-(1-methoxy-ethyl)-phenyl]-methyl-amino}-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.41 (d, J=6.6 Hz, 3H), 3.07 (s, 3H), 3.27 (s, 3H), 4.23-4.25 (m, 1H),7.01-7.04 (m, 4H), 7.20-7.24 (m, 4H), 7.86 (d, J=5.1 Hz, 1H), 8.50 (d,J=5.1 Hz, 1H), 8.69 (s, 1H). [M+H] Calc'd for C₂₃H₂₂N₄O₃, 403. Found,403.

Preparation 37A: methanesulfonic acid2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl ester

The title compound was prepared in 60% yield from2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propan-1-ol accordingto the procedure of Preparation 30A. [M+H] Calc'd for C₂₄H₂₇NO₄S, 426.Found, 426.

Preparation 37B:[4-(2-amino-isopropyl)phenyl]methyl[4-(phenylmethoxy)phenyl]amine

A solution of methanesulfonic acid2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl ester (3.5 g,8.24 mmol) in NH₃/THF (20 mL) was stirred overnight at 148° C. in asealed tube. The reaction mixture was concentrated and the residue waspurified by silica gel chromatography (DCM:MeOH, 10:1) to give 1.71 g(60%) of the title product. [M+H] Calc'd for C₂₃H₂₆N₂O, 347. Found, 347.

Preparation 37C:(2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl)-carbamic acidtert-butyl ester

A solution of[4-(2-amino-isopropyl)phenyl]methyl[4-(phenylmethoxy)phenyl]amine (1.7g, 4.91 mmol), (Boc)₂O (1.29 g, 5.90 mmol) and TEA (744 mg, 7.37 mmol)in THF (20 mL) was stirred for 2 h at RT. The reaction mixture wasconcentrated and the residue was purified by silica gel chromatography(PE:EA, 10:1) to give 1.67 g (76%) of the title product. [M+H] Calc'dfor C₂₈H₃₄N₂O₃, 447. Found, 447.

Preparation 37D:(2-{4-[(4-hydroxy-phenyl)-methyl-amino]-phenyl}-propyl)-carbamic acidtert-butyl ester

The title compound was prepared in 88% yield from(2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl)-carbamic acidtert-butyl ester according to the procedure of Preparation 36E. [M+H]Calc'd for C₂₁H₂₈N₂O₃, 357. Found, 357.

Example 37:2-(4-{[4-(2-amino-1-methyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 3.3% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and(2-{4-[(4-hydroxy-phenyl)-methyl-amino]-phenyl}-propyl)-carbamic acidtert-butyl ester according to the procedure of Example 23. ¹H NMR (300MHz, CD3OD-d₄): δ 1.28 (d, J=6.3 Hz, 3H), 2.73-2.96 (m, 2H), 3.32 (s,3H), 3.41-3.50 (m, 1H), 7.04-7.08 (m, 4H), 7.17-7.24 (m, 4H), 7.98 (d,J=4.8 Hz, 1H), 8.47 (d, J=4.8 Hz, 1H), 8.73 (s, 1H). [M+H] Calc'd forC₂₃H₂₃N₅O₂, 402. Found, 4 02.

Preparation 38A: (4-{2-[(2-methoxyethyl)amino]-isopropyl}phenyl)methyl[4(phenylmethoxy)phenyl]amine

A mixture of methanesulfonic acid2-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-propyl ester (1.22 g,2.88 mmol), 2-methoxy-ethylamine (1.08 g, 14.4 mmol) and NaHCO₃ (720 mg,8.64 mmol) in ACN (20 mL) was stirred overnight at 70° C. The reactionmixture was concentrated and the residue was purified by silica gelchromatography (DCM:MeOH, 10:1) to give 1.14 g (100%) of the titleproduct. [M+H] Calc'd for C₂₆H₃₂N₂O₂, 405. Found, 405.

Preparation 38B:(4-{2-[(2-methoxyethyl)methylamino]-isopropyl}phenyl)methyl[4-(phenylmethoxy)phenyl]amine

The title compound was prepared in 25% yield from(4-{2-[(2-methoxyethyl)amino]-isopropyl}phenyl)methyl[4(phenylmethoxy)phenyl]amine according to the procedure of Preparation27A. [M+H] Calc'd for C₂₇H₃₄N₂O₂, 419 Found, 419.

Preparation 38C:4-[(4-{2-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-ethyl}-phenyl)-methyl-amino]-phenol

The title compound was prepared in 100% yield from(4-{2-[(2-methoxyethyl)methylamino]-isopropyl}phenyl)methyl[4-(phenylmethoxy)phenyl]amineaccording to the procedure of Preparation 36E. [M+H] Calc'd forC₂₀H₂₈N₂O₂, 329. Found, 329.

Example 38:2-{4-[(4-{2-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-ethyl}-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 23% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[(4-{2-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-ethyl}-phenyl)-methyl-amino]-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, CD3OD-d₄): δ 1.12-1.14 (m, 3H), 2.59-2.60 (m, 1H), 2.72 (s, 3H),3.04-3.66 (m, 12H), 6.94-7.12 (m, 8H), 7.90-7.95 (m, 1H), 8.34-8.35 (m,1H), 8.73-8.74 (m, 1H). [M+H] Calc'd for C₂₇H₃₁N₅O₃, 474. Found, 474.

Preparation 39A: 1-(4-bromo-phenyl)-1-cyclopropyl-ethanol

To a solution of (4-bromo-phenyl)-cyclopropyl-methanone (225 mg, 1 mmol)in THF (10 mL) was added CH₃MgBr (0.4 mL, 1.1 mmol) at 0° C., and themixture was stirred for 2 h at RT. The reaction was quenched withaqueous NH₄Cl, extracted with EA (3×), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(PE:EA, 10:1) to give 179 mg (75%) of the title product. [M+H] Calc'dfor C₁₁H₁₃BrO, 241. Found, 241.

Preparation 39B: 1-bromo-4-(1-cyclopropyl-ethyl)-benzene

To a solution of 1-(4-bromo-phenyl)-1-cyclopropyl-ethanol (138 mg, 0.575mmol) in DCM (5 mL) at −78° C. was added under N₂ atmosphere Et₃SiH (87mg, 0.75 mmol) and TFA (131 mg, 1.15 mmol) and the mixture was stirredovernight at RT. The reaction was quenched with aqueous NaHCO₃,extracted with EA (3×), dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel chromatography (PE) to give 120mg (94%) of the title product. [M+H] Calc'd for C₁₁H₁₃Br, 225. Found,225.

Preparation 39C: [4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amine

A mixture of 1-bromo-4-(1-cyclopropyl-ethyl)-benzene (3.7 g, 16.52 mmol)and Cu (53 mg, 0.825 mmol) in a methylamine solution (40 wt. % in H₂O,35 mL) was stirred overnight at 100° C. in a sealed tube. The reactionwas cooled to RT, diluted with H₂O and extracted with EA (3×). Thecombined organics were washed with brine, dried over Na₂SO₄, filteredand concentrated. The residue was purified by silica gel chromatography(PE:EA, 10:1) to give 440 mg (15%) of the title product. [M+H] Calc'dfor C₁₂H₁₇N, 176. Found, 176.

Preparation 39D:4-{[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amino}-phenol

The title compound was prepared in 35% yield from[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amine according to the procedureof Preparation 5A. [M+H] Calc'd for C₁₈H₂₁NO, 268. Found, 268.

Example 39:2-(4-{[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 15% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-{[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amino}-phenol according tothe procedure for the preparation of Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 0.10-0.20 (m, 2H), 0.35-0.38 (m, 1H), 0.46-0.50 (m, 1H),0.89-0.93 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.91-1.97 (m, 1H), 3.23 (s,3H), 6.93 (d, J=9.0 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.16-7.25 (m, 4H),7.86 (d, J=4.5 Hz, 1H), 8.49 (d, J=4.5 Hz, 1H), 8.69 (s, 1H), 13.02 (s,1H). [M+H] Calc'd for C₂₅H₂₄N₄O₂, 413. Found, 413.

Preparation 40A: 3-(4-methoxy-phenylamino)-benzonitrile

The title compound was prepared in 55% yield from1-bromo-4-methoxy-benzene and 3-amino-benzonitrile according to theprocedure of Preparation 1A. [M+H] Calc'd for C₁₄H₁₂N₂O, 225. Found,225.

Preparation 40B: 3-[(4-methoxy-phenyl)-methyl-amino]-benzonitrile

The title compound was prepared in 67% yield from3-(4-methoxy-phenylamino)-benzonitrile according to the procedure ofPreparation 1B. [M+H] Calc'd for C₁₅H₁₄N₂O, 239. Found, 239.

Preparation 40C: 3-[(4-hydroxy-phenyl)-methyl-amino]-benzonitrile

The title compound was prepared in 39% yield from3-[(4-methoxy-phenyl)-methyl-amino]-benzonitrile according to theprocedure of Preparation 4B. [M+H] Calc'd for C₁₄H₁₂N₂O, 225. Found,225.

Example 40:3-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-benzonitrile

The title compound was prepared in 37% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and3-[(4-hydroxy-phenyl)-methyl-amino]-benzonitrile according to theprocedure for the preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ3.30 (s, 3H), 7.16-7.29 (m, 5H), 7.35-7.44 (m, 3H), 7.89 (d, J=5.1 Hz,1H), 8.53 (d, J=4.8 Hz, 1H), 8.72 (s, 1H). [M+H] Calc'd for C₂₁H₁₅N₅O₂,370. Found, 370.

Preparation 41A: 1-methyl-4-(3-nitro-benzyl)-piperazine

A mixture of 1-bromomethyl-3-nitro-benzene (5.0 g, 23 mmol),1-methyl-piperazine (2.3 g, 23 mmol) and K₂CO₃ (6.4 g, 46 mmol) in DMF(80 mL) was stirred overnight at RT. The reaction mixture was dilutedwith water and the mixture was extracted with EA (3×). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give 3.2 g (59%) of the title product without furtherpurification. [M+H] Calc'd for C₁₂H₁₇N₃O₂, 236. Found, 236.

Preparation 41B: 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine

A mixture of 1-methyl-4-(3-nitro-benzyl)-piperazine (3.20 g, 13.6 mmol),Fe (7.60 g, 136 mmol), NH₄Cl (364 mg, 6.81 mmol) in EtOH (40 mL) and H₂O(10 mL) was stirred for 2 h at 80° C. The mixture was concentrated,redissolved in methanol and filtered through celite. The filtrateconcentrated to give 1.3 g (46%) of the title product without furtherpurification. [M+H] Calc'd for C₁₂H₁₉N₃, 206. Found, 206.

Preparation 41C: methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound was prepared in 57% yield from3-(4-methyl-piperazin-1-ylmethyl)-phenylamine according to the procedureof Preparation 18A.

Preparation 41D:(4-benzyloxy-phenyl)-methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

To a solution of methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine(1.0 g, 4.6 mmol) in toluene (5 mL) was added1-benzyloxy-4-bromo-benzene (1.26 g, 4.79 mmol),biphenyl-2-yl-dicyclohexyl-phosphane (16 mg, 0.046 mmol), Pd₂(dba)₃ (42mg, 0.046 mmol) and t-BuOK (767 mg, 6.85 mmol), and the mixture wasstirred overnight at 110° C. under N₂ atmosphere. The reaction mixturewas filtered and concentrated. The residue was purified by silica gelchromatography (PE:EA, 20:1) to give 1.29 g (70%) of the title compound.[M+H] Calc'd for C₂₆H₃₁N₃O, 402. Found, 402.

Preparation 41E:4-{methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amino}-phenol

The title compound was prepared in 36% yield from(4-benzyloxy-phenyl)-methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amineaccording to the procedure of Preparation 36E. [M+H] Calc'd forC₁₉H₂₅N₃O, 312. Found, 312.

Example 41:2-(4-{methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 8% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-{methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amino}-phenolaccording to the procedure for the preparation of Example 1. ¹H NMR (300MHz, DMSO-d₆): δ 2.29 (s, 3H), 2.38-2.57 (m, 8H), 3.20 (s, 3H), 3.44 (s,2H), 6.86-7.04 (m, 5H), 7.16-7.26 (m, 3H), 7.82 (d, J=5.1 Hz, 1H), 8.44(d, J=5.1 Hz, 1H), 8.67 (s, 1H). [M+H] Calc'd for C₂₆H₂₈N₆O₂, 457.Found, 457.

Preparation 42A: (4-bromo-phenoxy)-tert-butyl-dimethyl-silane

The title compound was prepared in 90% yield from 4-bromo-phenolaccording to the procedure of Preparation 33A. [M+H] Calc'd forC₁₂H₁₉BrOSi, 288. Found, 288.

Preparation 42B:[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-cyclopropyl-phenyl)-methyl-amine

The title compound was prepared in 38% yield from(4-bromo-phenoxy)-tert-butyl-dimethyl-silane and(4-cyclopropyl-phenyl)-methyl-amine according to the procedure ofPreparation 41D. [M+H] Calc'd for C₂₂H₃₁NOSi, 354. Found, 354.

Preparation 42C: 4-[(4-cyclopropyl-phenyl)-methyl-amino]-phenol

The title compound was prepared in 28% yield from[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-cyclopropyl-phenyl)-methyl-amineaccording to the procedure of Preparation 33C. [M+H] Calc'd forC₁₆H₁₇NO, 240. Found, 240.

Example 42:2-{4-[(4-cyclopropyl-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 3% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[(4-cyclopropyl-phenyl)-methyl-amino]-phenol according to theprocedure for the preparation of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.60-0.63 (m, 2H), 0.86-0.90 (m, 2H), 1.86-1.88 (m, 1H), 3.23 (s, 3H),6.88-7.16 (m, 8H), 7.84-7.86 (m, 1H), 8.47-8.49 (m, 1H), 8.68 (s, 1H).[M+H] Calc'd for C₂₃H₂₀N₄O₂, 385. Found, 385.

MS Structure (ESI) Ex (prepared by procedure of cited Example) m/z NMRspectrum data 43

360 ¹H NMR (400 MHz, DMSO- d₆): δ 2.15 (s, 3H), 3.36 (s, 3H), 6.61 (d, J= 11.6 Hz, 1H), 7.32-7.34 (m, 5H), 7.87 (d, J = 6.4 Hz, 1H), 7.99 (s,1H), 8.50 (d, J = 6.8 Hz, 1H), 8.72 (s, 1H). 44

388 ¹H NMR (400 MHz, DMSO- d₆): δ 2.89 (s, 6H), 3.20 (s, 3H), 6.69 (d, J= 12.4 Hz, 2H), 6.78 (d, J = 12.4 Hz, 2H), 7.04-7.09 (m, 4H), 7.86 (d, J= 6.4 Hz, 1H), 8.50 (d, J = 6.8 Hz, 1H), 8.68 (s, 1H). 45

457 ¹H NMR (400 MHz, DMSO- d₆): δ 2.89 (s, 3H), 3.41 (s, 3H), 3.42-3.46(m, 4H), 3.72 (s, 2H), 6.51 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.4 Hz,2H), 6.99-7.20 (m, 5H), 7.86 (d, J = 5.2 Hz, 1H), 8.48 (d, J = 5.6 Hz,1H), 8.68 (s, 1H). 46

443 ¹H NMR (400 MHz, DMSO- d₆): δ 2.23 (s, 3H), 2.47-2.49 (m, 4H),3.10-3.12 (m, 4H), 3.21 (s, 3H), 6.74 (d, J = 12.0 Hz, 2H), 6.95 (d, J =12.0 Hz, 2H), 7.02-7.09 (m, 4H), 7.82 (d, J = 6.8 Hz, 1H), 8.45 (d, J =6.8 Hz, 1H), 8.67 (s, 1H). 47

388 ¹H NMR (400 MHz, DMSO- d₆): δ 2.87 (s, 6H), 3.32 (s, 3H), 6.38-6.44(m, 3H), 6.93- 6.96 (m, 2H), 7.13-7.17 (m, 3H), 7.86 (d, J = 6.4 Hz,1H), 8.47 (d, J = 6.8 Hz, 1H), 8.68 (s, 1H). 48

414 ¹H NMR (400 MHz, DMSO- d₆): δ 1.96 (m, 4H), 3.20 (s, 4H), 3.32 (s,3H), 6.57-6.66 (m, 4H), 7.03-7.08 (m, 4H), 7.86 (d, J = 4.8 Hz, 1H),8.50 (d, J = 4.8 Hz, 1H), 8.69 (s, 1H), 12.99 (s, 1H). 49

414 ¹H NMR (400 MHz, DMSO- d₆): δ 1.96 (m, 4H), 3.20 (m, 4H), 3.32 (s,3H), 6.25-6.35 (m, 3H), 6.94-7.18 (m, 5H), 7.87 (d, J = 4.8 Hz, 1H),8.51 (d, J = 4.8 Hz, 1H), 8.69 (s, 1H), 13.00 (s, 1H). 50

443 ¹H NMR (400 MHz, CD₃OD): δ 1.91-2.95 (m, 2H), 2.19-2.25 (m, 2H),3.25- 3.45 (m, 6H), 3.74-3.78 (m, 2H), 6.81-6.90 (m, 2H), 7.15- 7.33 (m,6H), 8.11 (d, J = 6.4 Hz, 1H), 8.53 (d, J = 6.4 Hz, 1H), 8.81 (s, 1H).51

373 ¹H NMR (400 MHz, DMSO- d₆): δ 1.50 (d, J = 9.2 Hz, 3H), 2.69 (s,3H), 5.14-5.16 (m, 1H), 6.85 (d, J = 9.6 Hz, 2H), 7.10 (d, J = 9.2 Hz,2H), 7.24-7.37 (m, 5H), 7.80 (d, J = 6.8 Hz, 1H), 8.48 (d, J = 7.2 Hz,1H), 8.67 (s, 1H), 13.05 (s, 1H). 52

373 ¹H NMR (400 MHz, DMSO- d₆): δ 1.50 (d, J = 9.2 Hz, 3H), 2.69 (s,3H), 5.14-5.16 (m, 1H), 6.85 (d, J = 9.6 Hz, 2H), 7.10 (d, J = 9.2 Hz,2H), 7.24-7.37 (m, 5H), 7.80 (d, J = 6.8 Hz, 1H), 8.48 (d, J = 7.2 Hz,1H), 8.67 (s, 1H), 13.05 (s, 1H). 53

377 ¹H NMR (400 MHz, DMSO- d₆): δ 2.14 (s, 3H), 3.25 (s, 3H), 6.69-6.77(m, 2H), 7.08- 7.26 (m, 5H), 7.86 (d, J = 6.4 Hz, 1H), 8.48 (d, J = 6.8Hz, 1H), 8.67 (s, 1H). 54

385 ¹H NMR (400 MHz, DMSO- d₆): δ 1.96-2.06 (m, 2H), 2.47-2.49 (m, 1H),3.36-3.53 (m, 3H), 3.67-3.70 (m, 1H), 6.59 (d, J = 12.4 Hz, 2H), 7.08(d, J = 12.4 Hz, 2H), 7.22-7.34 (m, 5H), 7.82 (d, J = 6.8 Hz, 1H), 8.43(d, J = 6.8 Hz, 1H), 8.63 (s, 1H). 55

444 ¹H NMR (300 MHz, DMSO- d₆): δ 2.19 (s, 3H), 2.77-2.80 (m, 4H), 3.24(s, 3H), 3.68- 3.71 (m, 4H), 6.69-6.73 (m, 2H), 6.80 (d, J = 12.0 Hz,2H), 7.09-7.14 (m, 3H), 7.81 (d, J = 6.4 Hz, 1H), 8.43 (d, J = 6.0 Hz,1H), 8.65 (s, 1H). 56

423 ¹H NMR (300 MHz, DMSO- d₆): δ 3.18 (s, 3H), 3.35 (s, 3H), 7.17-7.50(m, 8H), 7.87 (d, J = 6.4 Hz, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.70 (s,1H). 57

423 ¹H NMR (300 MHz, DMSO- d₆): δ 3.08 (s, 3H), 3.35 (s, 3H), 6.89 (d, J= 12.0 Hz, 2H), 7.37-7.44 (m, 4H), 7.68 (d, J = 12.0 Hz, 2H), 7.87 (d, J= 6.4 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.71 (s, 1H). 58

443 ¹H NMR (400 MHz, CD₃OD): δ 1.70-1.81 (m, 2H), 1.93-2.04 (m, 2H),3.11- 3.23 (m, 3H), 3.32 (s, 3H), 3.45-3.49 (m, 2H), 6.66-6.77 (m, 2H),7.02-7.24 (m, 6H), 8.19 (d, J = 6.8 Hz, 1H), 8.53 (d, J = 6.4 Hz, 1H),8.83 (s, 1H). 59

458 ¹H NMR (300 MHz, DMSO- d₆): δ 1.17 (t, J = 10.0 Hz, 3H), 2.60 (q, J= 10.0 Hz, 2H), 2.76-2.79 (m, 4H), 3.30 (s, 3H), 3.68-3.71 (m, 4H), 6.79(d, J = 9.2 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 7.14-7.17 (m, 3H), 7.85(d, J = 6.8 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.67 (s, 1H). 60

471 ¹H NMR (300 MHz, DMSO- d₆): δ 1.16 (t, J = 10.0 Hz, 3H), 2.25 (s,3H), 2.48-2.62 (m, 6H), 2.76-2.79 (m, 4H), 3.25 (s, 3H), 6.77 (d, J =8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 7.14-7.17 (m, 3H), 7.84 (d, J =6.4 Hz, 1H), 8.47 (d, J = 6.4 Hz, 1H), 8.66 (s, 1H). 61

431 ¹H NMR (300 MHz, DMSO- d₆): δ 3.28-3.36 (m, 7H), 3.66-3.69 (m, 4H),6.03-6.07 (m, 2H), 7.32-7.42 (m, 4H), 7.77 (d, J = 7.6 Hz, 1H), 7.89 (d,J = 7.6 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.71 (s, 1H), 13.15 (s, 1H).62

399 ¹H NMR (300 MHz, DMSO- d₆): δ 1.82- 1.86 (m, 1H), 2.07-2.17 (m, 1H),2.77-2.84 (m, 1H), 2.95- 3.02 (m, 1H), 3.30-3.36 (m, 4H), 3.52-3.55 (m,1H), 3.67- 3.72 (m, 1H), 6.79 (d, J = 9.6 Hz, 1H), 7.12-7.30 (m, 6H),7.80 (d, J = 5.2 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.68 (s, 1H), 13.00(s, 1H). 63

401 ¹H NMR (300 MHz, DMSO- d₆): δ 0.85 (d, J = 8.4 Hz, 6H), 1.75-1.82(m, 1H), 2.38 (d, J = 7.6 Hz, 2H), 3.22 (s, 3H), 6.93 (d, J = 11.6 Hz,2H), 7.01 (d, J = 10.8 Hz, 2H), 7.11 (d, J = 11.2 Hz, 2H), 7.17 (d, J =11.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.68(s, 1H), 13.01 (s, 1H). 64

403 ¹H NMR (300 MHz, DMSO- d₆): δ 1.40 (s, 6H), 3.26 (s, 3H), 4.93 (s,1H), 6.93 (d, J = 11.6 Hz, 2H), 7.03 (d, J = 11.2 Hz, 2H), 7.17 (d, J =12.0 Hz, 2H), 7.41 (d, J = 11.6 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 8.49(d, J = 6.8 Hz, 1H), 8.68 (s, 1H), 13.01 (s, 1H). 65

460 ¹H NMR (300 MHz, DMSO- d₆): δ 1.12 (t, J = 10.0 Hz, 3H), 2.52-2.60(m, 2H), 2.87 (s, 6H), 3.28 (s, 3H), 3.51 (t, J = 6.0 Hz, 2H), 4.26 (t,J = 6.0 Hz, 2H), 6.66-6.74 (m, 2H), 6.94 (d, J = 11.6 Hz, 2H), 7.10-7.19(m, 3H), 7.87 (d, J = 6.4 Hz, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.68 (s,1H). 66

447 ¹H NMR (300 MHz, DMSO- d₆): δ 1.11 (t, J = 10.0 Hz, 3H), 2.47-2.52(m, 2H), 3.26 (s, 3H), 3.32 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 4.03 (t,J = 6.0 Hz, 2H), 6.59-6.66 (m, 2H), 6.94 (d, J = 11.6 Hz, 2H), 7.06-7.17(m, 3H), 7.87 (d, J = 6.4 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.67 (s,1H). 67

431 ¹H NMR (400 MHz, DMSO- d₆): δ 1.22 (s, 6H), 3.20 (s, 3H), 3.30 (s,3H), 3.32 (s, 2H), 6.93 (d, J = 11.6 Hz, 2H), 7.01 (d, J = 11.2 Hz, 2H),7.19 (d, J = 11.6 Hz, 2H), 7.31 (d, J = 11.2 Hz, 2H), 7.86 (d, J = 6.4Hz, 1H), 8.48 (d, J = 6.4 Hz, 1H), 8.67 (s, 1H). 68

417 ¹H NMR (400 MHz, DMSO- d₆): δ 1.20 (s, 6H), 3.25 (s, 3H), 3.38 (s,2H), 6.93 (d, J = 12.0 Hz, 2H), 7.01 (d, J = 11.2 Hz, 2H), 7.16 (d, J =12.0 Hz, 2H), 7.31 (d, J = 11.2 Hz, 2H), 7.84 (d, J = 6.8 Hz, 1H), 8.48(d, J = 6.4 Hz, 1H), 8.67 (s, 1H). 69

387 ¹H NMR (400 MHz, DMSO- d₆): δ 0.88 (t, J = 9.6 Hz, 3H), 1.53-1.57(m, 2H), 2.49 (J = 6.8 Hz, 2H), 3.24 (s, 3H), 6.93 (d, J = 11.2 Hz, 2H),7.01 (d, J = 11.2 Hz, 2H), 7.12-7.17 (m, 4H), 7.85 (d, J = 6.4 Hz, 1H),8.48 (d, J = 6.4 Hz, 1H), 8.67 (s, 1H). 70

416 ¹H NMR (400 MHz, DMSO- d₆): δ 1.25 (d, J = 8.4 Hz, 3H), 2.71 (s,3H), 3.08 (d, J = 8.4 Hz, 2H), 3.21-3.23 (m, 1H), 3.32 (s, 3H),7.05-7.26 (m, 8H), 7.24 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 7.2 Hz, 1H),8.87 (s, 1H). 71

416 ¹H NMR (400 MHz, DMSO- d₆): δ 1.18 (d, J = 7.2 Hz, 3H), 1.76-1.79(m, 2H), 2.52- 2.58 (m, 1H), 2.69-2.72 (m, 2H), 3.23 (s, 3H), 6.88- 7.11(m, 8H),, 7.67 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 4.8 Hz, 1H), 8.57 (s,1H). 72

430 ¹H NMR (400 MHz, DMSO- d₆): δ 1.18 (d, J = 7.2 Hz, 3H), 1.76-1.79(m, 2H), 2.48 (s, 3H), 2.58-2.72 (m, 3H), 3.26 (s, 3H), 6.88-7.11 (m,8H), 7.67 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H).73

443 ¹H NMR (300 MHz, DMSO- d₆): δ 3.23 (s, 3H), 4.68-4.77 (m, 2H), 6.82(d, J = 11.6 Hz, 2H), 7.06-7.15 (m, 6H), 7.87 (d, J = 6.4 Hz, 1H), 8.48(d, J = 6.0 Hz, 1H), 8.67 (s, 1H), 13.01 (s, 1H). 74

417 ¹H NMR (400 MHz, DMSO- d₆): δ 0.96 (d, J = 9.2 Hz, 6H), 1.94-2.01(m, 1H), 3.20 (s, 3H), 3.71 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 12.4 Hz,2H), 6.94 (d, J = 12.0 Hz, 2H), 7.06-7.10 (m, 4H), 7.81 (d, J = 6.4 Hz,1H), 8.43 (d, J = 6.4 Hz, 1H), 8.64 (s, 1H). 75

431 ¹H NMR (400 MHz, DMSO- d₆): δ 0.96 (s, 9H), 3.21 (s, 3H), 3.60 (s,2H), 6.74 (d, J = 12.4 Hz, 2H), 6.94 (d, J = 12.0 Hz, 2H), 7.06-7.10 (m,4H), 7.84 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 6.4 Hz, 1H), 8.66 (s, 1H).76

399 ¹H NMR (400 MHz, DMSO- d₆): δ 0.17-0.20 (m, 2H), 0.43-0.48 (m, 2H),0.92-0.96 (m, 1H), 2.44 (s, 3H), 3.27 (d, J = 9.2 Hz, 2H), 6.94 (d, J =12.0 Hz, 2H), 7.03 (d, J = 12.0 Hz, 2H), 7.15-7.23 (m, 4H), 7.86 (d, J =6.8 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.68 (s, 1H), 13.02 (s, 1H). 77

401 ¹H NMR (300 MHz, DMSO- d₆): δ 0.77 (t, J = 7.2 Hz, 3H), 1.17 (d, J =7.2 Hz, 3H), 1.50-1.55 (m, 2H), 2.48-2.55 (m, 1H), 3.27 (d, J = 13.5 Hz,3H), 6.92 (d, J = 9.3 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.15-7.29 (m,4H), 7.86 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.68 (s, 1H),13.02 (s, 1H). 78

401 ¹H NMR (300 MHz, DMSO- d₆): δ 0.77 (t, J = 7.2 Hz, 3H), 1.17 (d, J =7.2 Hz, 3H), 1.50-1.55 (m, 2H), 2.48-2.55 (m, 1H), 3.27 (d, J = 13.5 Hz,3H), 6.92 (d, J = 9.3 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.15-7.29 (m,4H), 7.86 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.68 (s, 1H),13.02 (s, 1H). 79

442 H NMR (300 MHz, DMSO- d₆): δ 2.22 (s, 3H), 3.08-3.11 (m, 4H), 3.25(s, 3H), 3.32- 2.39 (m, 4H), 6.48 (d, J = 8.4 Hz, 1H), 6.93-6.96 (m,2H), 6.94 (d, J = 9.3 Hz, 2H), 7.13-7.17 (m, 3H), 7.83 (d, J = 5.1 Hz,1H), 8.46 (d, J = 5.1 Hz, 1H), 8.66 (s, 1H). 80

358 H NMR (300 MHz, DMSO- d₆): δ 1.17 (t, J = 2.1 Hz, 3H), 3.74-3.81 (m,2H), 6.95-7.03 (m, 5H), 7.20-7.23 (m, 2H), 7.31 (t, J = 7.2 Hz, 2H),7.87 (d, J = 5.1 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.71 (s, 1H). 81

369 H NMR (300 MHz, DMSO- d₆): δ 3.39 (s, 3H), 6.81 (d, J = 2.4 Hz, 2H),7.33-7.43 (m, 4H), 7.54-7.59 (m, 2H), 7.87 (d, J = 4.8 Hz, 1H), 8.51(brs, 1H), 8.71 (brs, 1H), 13.13 (brs, 1H). 82

398 H NMR (300 MHz, DMSO- d₆): δ 3.29 (s, 3H), 4.13 (s, 3H), 6.82 (d, J= 9.3 Hz, 2H), 7.03 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 7.42(s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 5.1 Hz, 1H), 8.23 (s,1H), 8.49 (d, J = 4.5 Hz, 1H), 8.68 (s, 1H). 83

372 H NMR (300 MHz, DMSO- d₆): δ 2.17 (d, J = 2.4 Hz, 6H), 3.22 (s, 3H),6.83-6.87 (m, 4H), 7.08-7.14 (m, 3H), 7.83 (d, J = 4.8 Hz, 1H), 8.47 (d,J = 5.1 Hz, 1H), 8.66 (s, 1H). 84

372 ¹H NMR (300 MHz, DMSO- d₆): δ 1.16 (t, J = 7.2 Hz, 3H), 2.55-2.60(m, 2H), 3.23 (s, 3H), 6.90 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz,2H), 7.14-7.18 (m, 4H), 7.85 (d, J = 5.7 Hz, 1H), 8.48 (d, J = 5.7 Hz,1H), 8.67 (s, 1H). 85

386 ¹H NMR (300 MHz, DMSO- d₆): δ 1.18 (d, J = 7.5 Hz, 6H), 2.80-2.89(m, 1H), 3.24 (s, 3H), 6.92 (d, J = 9.3 Hz, 2H), 7.02 (d, J = 9.3 Hz,2H), 7.14-7.21 (m, 4H), 7.84 (d, J = 5.1 Hz, 1H), 8.47 (d, J = 5.1 Hz,1H), 8.67 (s, 1H). 86

412 ¹H NMR (300 MHz, DMSO- d₆): δ 3.31 (s, 3H), 7.10-7.15 (m, 3H), 7.23(d, J = 9.0 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H),7.87 (d, J = 5.1 Hz, 1H), 8.50 (d, J = 4.5 Hz, 1H), 8.69 (s, 1H). 87

412 ¹H NMR (300 MHz, DMSO- d₆): δ 3.32 (s, 3H), 6.94 (d, J = 6.6 Hz,2H), 7.34 (d, J = 6.6 Hz, 2H), 7.40 (d, J = 6.3 Hz, 2H), 7.53 (d, J =6.6 Hz, 2H), 7.90 (d, J = 3.6 Hz, 1H), 8.53 (d, J = 3.9 Hz, 1H), 8.73(s, 1H). 88

456 ¹H NMR (300 MHz, DMSO- d₆): δ 1.86-1.89 (m, 2H), 2.32 (s, 3H),2.48-2.53 (m, 2H), 2.67 (m, 2H), 3.24 (s, 3H), 3.31-3.38 (m, 2H),3.47-3.48 (m, 2H), 6.30-6.39 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H),7.08-7.13 (m, 3H), 7.80 (d, J = 4.5 Hz, 1H), 8.42 (d, J = 5.1 Hz, 1H),8.64 (s, 1H). 89

470 ¹H NMR (300 MHz, DMSO- d₆): δ 1.56-1.59 (m, 2H), 1.71-1.76 (m, 2H),2.14-2.21 (m, 2H), 2.25 (s, 3H), 2.66 (s, 3H), 2.92 (d, J = 11.7 Hz,2H), 3.23 (s, 3H), 3.36-3.38 (m, 1H), 6.34-6.37 (m, 1H), 6.43-6.49 (m,2H), 6.91-6.94 (m, 2H), 7.07-7.13 (m, 3H), 7.81 (d, J = 5.1 Hz, 1H),8.42 (d, J = 5.1 Hz, 1H), 8.65 (s, 1H). 90

456 ¹H NMR (300 MHz, DMSO- d₆): δ 2.21 (s, 3H), 2.24 (s, 3H), 2.49-2.50(m, 4H), 3.09- 3.10 (m, 4H), 3.24 (s, 3H), 6.35 (s, 1H), 6.45 (d, J =4.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.86(d, J = 4.8 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.68 (s, 1H). 91

363 ¹H NMR (300 MHz, DMSO- d₆): δ 1.92-2.08 (m, 4H), 3.58 (t, J = 8.7Hz, 2H), 4.00-4.03 (m, 2H), 4.64-4.71 (m, 1H), 9.49 (s, 1H), 7.05 (d, J= 1.5 Hz, 1H), 7.42 (s, 1H), 7.61- 7.63 (m, 2H), 7.82 (d, J = 3.9 Hz,1H), 8.43 (d, J = 3.9 Hz, 1H), 8.60 (s, 1H). 92

400 ¹H NMR (400 MHz, DMSO- d₆): δ 1.28 (s, 9H), 3.27 (s, 3H), 6.95 (d, J= 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.36(d, J = 8.0 Hz, 2H), 7.87 (s, 1H), 8.47 (m, 1H), 8.72 (m, 1H), 13.05 (s,1H). 93

386 ¹H NMR (300 MHz, DMSO- d₆): δ 1.20 (d, J = 6.8 Hz, 6H), 2.85 (m,1H), 3.29 (s, 3H), 6.89-7.01 (m, 5H), 7.20- 7.25 (m, 3H), 7.88 (s, 1H),8.52-8.73 (m, 2H), 13.07 (s, 1H). 94

379 ¹H NMR (300 MHz, DMSO- d₆): δ 3.28 (s, 3H), 6.99 (d, J = 9.0 Hz,2H), 7.13 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 7.30 (d, J =9.0 Hz, 2H), 7.86 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.70(s, 1H). 95

379 ¹H NMR (300 MHz, DMSO- d₆): δ 3.32 (s, 3H), 6.85-6.92 (m, 3H),7.21-7.26 (m, 3H), 7.34 (d, J = 5.1 Hz, 2H), 7.89 (d, J = 3.9 Hz, 1H),8.52 (d, J = 3.9 Hz, 1H), 8.72 (s, 1H), 13.11 (s, 1H). 96

363 ¹H NMR (300 MHz, DMSO- d₆): δ 3.36 (s, 3H), 6.70 (d, J = 8.1 Hz,2H), 7.13 (d, J = 8.1 Hz, 2H), 7.29-7.40 (m, 4H), 7.85 (s, 1H),8.47-8.49 (br, 1H), 8.65-8.70 (br 1H). 97

374 ¹H NMR (300 MHz, DMSO- d₆): δ 1.14 (t, J = 7.5 Hz, 3H), 2.45-2.47(m, 2H), 3.36 (s, 3H), 8.64 (d, J = 8.7 Hz, 1H), 7.36-7.40 (m, 5H), 7.89(d, J = 5.1 Hz, 1H), 8.03 (s, 1H), 8.53 (d, J = 4.5 Hz, 1H), 874 (s,1H), 13.16 (s, 1H). 98

427 ¹H NMR (300 MHz, DMSO- d₆): δ 2.43-2.50 (m, 2H), 3.23 (s, 3H),3.80-3.84 (m, 2H), 4.21-4.22 (m, 2H), 6.16 (s, 1H), 7.01-7.10 (m, 4H),7.24- 7.41 (m, 4H), 7.88 (d, J = 4.8 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H),8.72 (s, 1H), 13.02 (s, 1H). 99

429 H NMR (300 MHz, DMSO- d₆): δ 1.65-1.68 (m, 4H), 2.49-2.51 (m, 1H),3.26 (s, 3H), 3.40-3.41 (m, 2H), 3.91- 3.94 (m, 2H), 6.93-7.05 (m, 4H),7.16-7.22 (m, 4H), 7.85 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H),8.68 (s, 1H), 13.07 (s, 1H). 100

460 ¹H NMR (300 MHz, CD3OD-d₄): δ 1.19-1.26 (m, 3H), 2.64-2.70 (m, 1H),3.07- 3.66 (m, 12H), 7.07-7.20 (m, 8H), 8.00-8.05 (m, 1H), 8.47- 8.50(m, 1H), 8.75-8.77 (m, 1H). 101

415 ¹H NMR (300 MHz, DMSO- d₆): δ 0.29-0.31 (m, 2H), 0.54-0.57 (m, 2H),1.20-1.21 (m, 1H), 3.21 (s, 3H), 3.79 (d, J = 7.2 Hz, 2H), 6.74 (d, J =9.0 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.09-7.12 (m, 4H), 7.85 (d, J =5.1 Hz, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.67 (s, 1H), 13.00 (s, 1H). 102

413 ¹H NMR (300 MHz, CD3OD-d₄): δ 1.25 (d, J = 6.9 Hz, 6H), 2.86-2.88(m, 1H), 3.34 (s, 3H), 3.60 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 5.7 Hz,2H), 6.95 (d, J = 9.0 Hz, 2H), 7.06-7.13 (m, 4H), 7.20 (d, J = 8.7 Hz,2H), 7.98 (d, J = 5.1 Hz, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.75 (s, 1H).103

355 1H NMR (400 MHz, DMSO- d6): δ 6.75 (d, J = 2.4 Hz, 1H), 7.16 (d, J =8.4 Hz, 1H), 7.44 (t, J = 6.4 Hz, 1H), 7.61- 7.65 (m, 6H), 7.76 (d, J =3.2 Hz, 1H), 7.89 (s, 1H), 8.50- 8.67 (m, 2H), 13.10 (s, 1H). 104

362 1H NMR (400 MHz, DMSO- d6): δ 1.63-1.88 (m, 4H), 2.58-2.67 (m, 2H),3.01-3.10 (m, 2H), 4.27-4.30 (m, 1H), 6.46 (d, J = 2.0 Hz, 1H), 7.01 (d,J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.62 (d, J =8.8 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 4.8 Hz, 1H), 8.64(s, 1H). 105

457 1H NMR (300 MHz, DMSO- d6): δ 2.18 (s, 3H), 2.25 (s, 3H), 2.48-2.49(m, 4H), 2.80- 2.85 (m ,4H), 3.24 (s, 3H), 6.69-6.73 (m, 2H), 6.90 (d, J= 5.7 Hz, 2H), 7.09-7.14 (m, 3H), 7.83 (d, J = 5.1 Hz), 8.46 (d, J = 5.1Hz), 8.66 (s, 1H). 106

426 ¹H NMR (400 MHz, DMSO- d₆): δ ppm 3.28-3.31 (m, 3 H) 3.49-3.63 (m, 2H) 6.98- 7.06 (m, 2 H) 7.08-7.15 (m, 2 H) 7.26 (br. s., 4 H) 7.81- 7.94(m, 1 H) 8.44-8.58 (m, 1H) 8.65-8.79 (m, 1 H) 12.78-13.25 (s, 1 H) 107

452 ¹H NMR (400 MHz, DMSO- d₆): δ ppm 1.02-1.13 (m, 2 H) 1.22-1.38 (m, 2H) 2.48- 2.50 (m, 3 H) 6.95-7.03 (m, 2 H) 7.13-7.19 (m, 2 H) 7.27- 7.39(m, 4 H) 7.85-7.93 (m, 1 H) 8.47-8.57 (m, 1 H) 8.70-8.75 (m, 1 H) 13.02-13.18 (s, 1 H) 108

440 ¹H NMR (400 MHz, DMSO- d₆): δ ppm 1.38-1.47 (m, 3 H) 3.29-3.31 (s, 3H) 3.62- 3.79 (m, 1 H) 6.98-7.07 (m, 2 H) 7.09-7.17 (m, 2 H) 7.23- 7.36(m, 4 H) 7.84-7.93 (s, 1 H) 8.45-8.59 (s, 1 H) 8.65- 8.79 (s, 1 H)12.98-13.20 (s, 1 H) 109

387 ¹H NMR (400 MHz, DMSO- d₆): δ ppm 1.19-1.27 (m, 6 H) 2.47-2.49 (m, 3H) 2.93- 3.09 (m, 1 H) 7.02-7.09 (m, 2 H) 7.21-7.30 (m, 3 H) 7.40- 7.49(m, 1 H) 7.85-7.93 (m, 1 H) 8.23-8.32 (m, 1 H) 8.48-8.58 (m, 1 H) 8.66-8.77 (m, 1 H) 13.01-13.16 (s, 1 H) 110

429 H NMR (300 MHz, DMSO- d₆): δ ppm 3.29 (s, 3 H) 7.02- 7.05 (m, 2 H)7.13-7.16 (m, 2 H) 7.23-7.30 (m, 4 H) 7.86- 7.88 (m, 1 H) 8.50-8.52 (m,1 H) 8.70 (s, 1 H) 13.10 (s, 1 H) 111

403 H NMR (300 MHz, DMSO- d₆): δ ppm 1.25 (d, J = 8.0 Hz, 6H), 3.21 (s,3 H), 4.51-4.59 (m, 1H), 6.75 (d, J = 12.0 Hz, 2H), 6.92 (d, J = 12.0Hz, 2H), 7.08-7.13 (m, 4 H), 7.85 (d, J = 6.8 Hz, 1 H), 8.48 (d, J = 6.8Hz, 1 H) 8.67 (s, 1 H) 12.98 (s, 1 H) 112

422 ¹H NMR (400 MHz, DMSO- d₆): δ 1.20 (d, J = 8.0 Hz, 6H), 1.81-1.83(m, 1H), 2.19- 2.21 (m, 1H), 2.87-2.92 (m, 1H), 3.58-3.65 (m, 3H), 3.90-3.95 (m, 1H), 4.58-4.62 (m, 1H), 6.76 (d, J = 12.0 Hz, 2H), 6.97 (d, J =12.0 Hz, 2H), 7.19 (d, J = 12.0 Hz, 2H), 7.25 (d, J = 12.0 Hz, 2H), 7.87(d, J = 6.4 Hz, 1H), 8.52 (dd, J = 2.0 Hz, 3.2 Hz, 1H), 8.69 (s, 1H),13.02 (s, 1H). 113

426 1H NMR (300 MHz, DMSO- d₆): δ 1.22 (d, J = 7.2 Hz, 6H), 1.58-1.77(m, 4H), 2.20- 2.24 (m, 2H), 2.87-2.91 (m, 1H), 4.29 (t, J = 7.8 Hz,1H), 6.71 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 7.14 (d, J =8.7 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.86 (d, J = 4.8 Hz, 1H),8.48-8.50 (m, 1H), 8.69 (s, 1H), 13.01 (brs, 1H).

Preparation 114A: 2,2,2-trifluoro-N-(4-isopropyl-phenyl)-acetamide

To a solution of 4-isopropyl-phenylamine (1.0 g, 7.4 mmol) in DCM (60ml) was added pyridine (1.8 g, 22.2 mmol) and TFAA (1.9 g, 8.9 mmol) at0° C., and the mixture was stirred for 2 h at RT. The reaction wasquenched with aqueous NaHCO₃ and the mixture was extracted with EA (80mL×3). The combined organics were dried over MgSO₄ and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography (PE:EtOAc, 30:1) to give the title compound (1.6 g, 94%)as a yellow oil. [M+H] Calc'd for C₁₁H₁₂F₃NO, 232. Found, 232.

Preparation 114B: (4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amine

To a solution of 2,2,2-trifluoro-N-(4-isopropyl-phenyl)-acetamide (1.6g, 7.0 mmol) in THF (70 mL) was added DMSB (7 mL, 14.0 mmol) and themixture was refluxed for 2 h. The reaction was quenched with H₂O (70mL), extracted with ether (80 mL×3). The combined organics were driedover MgSO₄ and concentrated in vacuo. The resulting residue was purifiedby silica gel column chromatography (PE:EtOAc, 50:1) to give the titlecompound (800 mg, 53%) as a yellow oil. [M+H] Calc'd for C₁₁H₁₄F₃N, 218.Found, 218.

Preparation 114C:4-[(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amino]-phenol

The title compound was prepared in 73% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amine according to theprocedure of Preparation 33C. [M+H] Calc'd for C₁₇H₁₈F₃NO, 310. Found,310.

Example 114:2-{4-[(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 11% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-[(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amino]-phenol accordingto the procedure for the preparation of Example 1; ¹H NMR (300 MHz,DMSO-d₆): δ 1.20-1.22 (m, 6H), 2.88-2.89 (m, 1H), 4.59-4.62 (m, 2H),6.94 (d, J=5.4 Hz, 2H), 7.07-7.10 (d, J=8.4 Hz, 2H), 7.25 (m, 4H),7.86-7.88 (d, J=4.5 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.70 (s, 1H). [M+H]Calc'd for C₂₄H₂₁F₃N₄O₂, 455. Found, 455.

Preparation 115A:[4-(3-amino-1-methylpropyl)phenyl]methyl[4-(phenylmethoxy)phenyl]amine

To a solution of3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyronitrile (1.0 g,2.8 mmol) in THF (10 mL) was added LAH (2.3 mL, 2.4M) at 0° C., and themixture was stirred at RT for 2 h. The reaction was quenched with waterand extracted with EA (3×). The combined organics were dried over MgSO₄and concentrated to give 0.68 g (68%) of the title compound. [M+H]Calc'd for C₂₄H₂₈N₂O, 361. Found, 361.

Preparation 115B:(3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyl)-carbamic acidtert-butyl ester

To a solution of[4-(3-amino-1-methylpropyl)phenyl]methyl[4-(phenylmethoxy)phenyl]amine(0.68 g, 1.9 mmol) in DCM (5 mL) was added (Boc)₂O (0.5 g, 2.3 mmol) andTEA (0.38 g, 3.8 mmol), and the mixture was stirred at RT for 2 h. Thereaction was quenched with aqueous NH₄Cl and extracted with DCM (3×).The combined organics were dried over MgSO₄ and concentrated to give0.83 g (95%) of the title compound. [M+H] Calc'd for C₂₉H₃₆N₂O₃, 461.Found, 461.

Preparation 115C:(3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyl)-methyl-carbamicacid tert-butyl ester

To a solution of(3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyl)-carbamic acidtert-butyl ester (1.9 g, 4.1 mmol) in THF (20 mL) was added NaH (0.25 g,6.15 mmol) at 0° C., and the mixture was stirred at RT for 30 min at 0°C. CH₃I (0.7 g, 4.92 mmol) was added and the mixture was stirred at 45°C. for 2 h. The reaction was quenched with aqueous NH₄Cl and extractedwith EA (3×). The combined organics were dried over MgSO₄ andconcentrated. The residue was purified by silica gel chromatography(EA:PE, 1:10) give 1.2 g (61%) of the title compound. [M+H] Calc'd forC₃₀H₃₈N₂O₃, 475. Found, 475.

Preparation 115D:4-{[4-(3-dimethylamino-1-methyl-propyl)-phenyl]-methyl-amino}-phenol

To a solution of(3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-phenyl}-butyl)-methyl-carbamicacid tert-butyl ester (0.89 g, 1.88 mmol) in THF (10 mL) was added LAH(1.2 mL, 2.4M) at 0° C., and the mixture was refluxed overnight. Thereaction was quenched with water and extracted with EA (3×). Thecombined organics were dried over MgSO₄ and concentrated. The residuewas dissolved in MeOH and Pd/C (30 mg) was added. The mixture wasstirred overnight at RT under H₂ atmosphere and filtered. The filtratewas concentrated and the residue was purified by silica gelchromatography (MeOH:DCM, 1:10) to give 0.4 g (72%) of the titlecompound. [M+H] Calc'd for C₁₉H₂₆N₂O, 299. Found, 299.

Example 115:2-(4-{[4-(3-dimethylamino-1-methyl-propyl)-phenyl]-methyl-amino}-phenoxy)-pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 5% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol andN-(4-hydroxy-phenyl)-N-methyl-2-phenyl-acetamide according to theprocedure for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆):δ1.02 (d, J=8.4 Hz, 3H), 2.25-2.27 (m, 1H), 2.44-2.52 (m, 1H), 2.67-2.73(m, 1H), 2.88 (d, J=26.0 Hz, 6H), 3.04-3.08 (m, 2H), 3.30 (s, 3H),7.00-7.20 (m, 8H), 7.87 (d, J=6.8 Hz, 1H), 8.50 (d, J=6.8 Hz, 1H), 8.67(s, 1H). [M+H] Calc'd for C₂₆H₂₉N₅O₂, 444. Found, 444.

Preparation 116A: 1-bromo-2-(2-methyl-allyloxy)-4-nitro-benzene

To a solution of 2-bromo-5-nitro-phenol (0.5 g, 2.3 mmol) in acetone (20mL) was added 3-bromo-2-methyl-propene (465 mg, 3.4 mmol) and K₂CO₃ (633mg, 4.6 mmol), and the mixture was refluxed overnight. The reactionmixture was cooled to RT and the solvent was concentrated. The residuewas dissolved in EA, washed with water, washed with brine. The organicswere concentrated and purified by silica gel chromatography (EA: PE,1:20) to give 0.5 g (80%) of the title compound. [M+H] Calc'd forC₁₀H₁₀BrNO₃, 271. Found, 271.

Preparation 116B: [4-bromo-3-(2-methyl-allyloxy)-phenyl]-carbamic acidtert-butyl ester

To a solution of 1-bromo-2-(2-methyl-allyloxy)-4-nitro-benzene (3.1 g,114 mmol) in methanol (100 mL) was added iron powder (1.95 g, 343 mmol)and NH₄Cl (2.0 g, 37 mmol), and the mixture was refluxed overnight, thesolvent was concentrated. The residue was adjusted with aqueous NaHCO₃to PH-8, extracted with EA (3×). The combined organics were dried andconcentrated. The residue was dissolved in THF (50 mL), (Boc)₂O (3.0 g,137 mmol) and TEA (2.5 g, 228 mmol) were added, and the mixture wasrefluxed overnight. The reaction mixture was cooled to RT and thesolvent was concentrated. The residue was purified by silica gelchromatography (EA:PE, 1:20) to give 3.0 g (77%) of the title compound.[M+H] Calc'd for C₁₅H₂₀BrNO₃, 342. Found, 342.

Preparation 116C: (3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-carbamicacid tert-butyl ester

To a solution of [4-bromo-3-(2-methyl-allyloxy)-phenyl]-carbamic acidtert-butyl ester (340 mg, 1 mmol) in toluene (10 mL) was added was AIBI(16.5 mg, 0.1 mmol) and tributytin hydride (360 mg, 1.2 mmol), and themixture was stirred overnight at 110° C. The reaction mixture was cooledto RT, EA and 10% KF solution were added and the mixture was stirred for2 h. The organic layer was washed with water, washed with brine andconcentrated. The residue was purified by silica gel chromatography(PE:EA, 20:1) to give 150 mg (57%) of the title compound. [M+H] Calc'dfor C₁₅H₂₁NO₃, 264. Found, 264.

Preparation 116D:(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-amine

To a solution of (3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-carbamicacid tert-butyl ester (1.0 g, 3.8 mmol) in DMF (10 mL) was added NaH(0.23 g, 5.7 mmol) at 0° C., and the mixture was stirred for 30 min at0° C. CH₃I (0.65 g, 4.5 mmol) was added and the mixture was stirred atRT for 2 h, quenched with aqueous NH₄Cl, and extracted with EA (3×). Thecombined organics were washed with water, washed with brine, dried andconcentrated. The residue was dissolved in DCM (10 mL), TFA (2 mL) wasadded and the mixture was stirred at RT for 1 h. The organics wereconcentrated and the residue was purified by silica gel chromatography(EA:PE, 1:20) to give 600 mg (94%) of the title compound. [M+H] Calc'dfor C₁₁H₁₅NO, 178. Found, 178.

Preparation 116E:4-[(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-amino]-phenol

A solution of (3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-amine(300 mg, 1.7 mmol), 1-benzyloxy-4-bromo-benzene (535 mg, 2.0 mmol),S-Phos (35 mg, 0.085 mmol), Pd₂(dba)₃ (80 mg, 0.085 mmol), t-BuOK (475mg, 4.25 mmol) in toluene (10 mL) was refluxed overnight under nitrogenatmosphere. The solvent was concentrated and the residue was purified bysilica gel chromatography (EA:PE, 1:20) to give(4-benzyloxy-phenyl)-(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-amine(600 mg, 99%). This benzyl protected product was in turn dissolved inTHF/MeOH and Pd/C (50 mg) was added. The mixture was stirred overnightat RT under H₂ atmosphere. The mixture was filtered on celite and thefiltrate was concentrated. The residue was purified by silica gelchromatography (EA:PE, 1:10) to give 430 mg (94%) of the title compound.[M+H] Calc'd for C₁₇H₁₉NO₂, 270. Found, 270.

Example 116:(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-[4-(4-methyl-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-amine

The title compound was prepared in 48% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol andN-(4-hydroxy-phenyl)-N-methyl-2-phenyl-acetamide according to theprocedure for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.26 (s, 6H), 3.22 (s, 3H), 4.19 (s, 2H), 6.46-6.57 (m, 2H), 6.97 (d,J=7.6 Hz, 1H), 7.10 (d, J=10.8 Hz, 1H), 7.19 (d, J=10.8 Hz, 2H), 7.86(d, J=6.0 Hz, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.69 (s, 1H), 13.04 (s, 1H).[M+H] Calc'd for C₂₂H₁₈N₄O₃, 387. Found, 387.

Preparation 117A: 4-(benzyloxy)-N-(4-isopropylphenyl)aniline

A mixture of 4-(benzyloxy)aniline (7.8 g, 39.03 mmol),1-bromo-4-isopropylbenzene (8.5 g, 42.93 mmol), X-Phos (2.3 g, 4.68mmol), Pd(OAc)₂ (0.53 g, 2.34 mmol) and Cs₂CO₃ (50.9 g, 156.12 mmol) intoluene (150 mL) was purged with N₂ and then reflux overnight. Thereaction mixture was cooled to RT and filtered. The filtrate wasconcentrated and purified by silica column chromatography (PE:EA, 20:1)to give 7.1 g (57%) of the title compound. ¹H NMR (CDCl₃, 300 MHz): δ1.23 (d, J=6.9 Hz, 6H), 2.77-2.92 (m, 1H), 5.04 (s, 2H), 6.87-6.94 (m,4H), 7.01-7.04 (m, 2H), 7.08-7.10 (m, 2H), 7.31-7.46 (m, 5H). [M+H]Calc'd for C₂₂H₂₃NO, 318. Found, 318.

Preparation 117B: 4-(benzyloxy)-N-ethyl-N-(4-isopropylphenyl)aniline

To a solution of compound 4-(benzyloxy)-N-(4-isopropylphenyl)aniline(0.5 g, 1.58 mmol) in DMF (5 mL) was added NaH (189 mg, 4.73 mmol) andthe mixture was stirred at 0° C. for 30 min. Iodoethane (761 mg, 4.9mmol) was then added and the reaction mixture was stirred overnight atRT. The mixture was quenched with aqueous NH₄Cl solution and extractedwith ethyl acetate (3×10 mL). The combined organic layers were washedwith water (3×10 mL), washed with brine (10 mL), dried over Na₂SO₄ andconcentrated to give 350 mg (64%) of the title compound as brown liquid.¹H NMR (CDCl₃, 300 MHz): δ 1.19 (t, J=6.9 Hz, 3H), 1.22 (d, J=6.9 Hz,6H), 2.76-2.90 (m, 1H), 3.69 (q, J=6.9 Hz, 2H), 5.06 (s, 2H), 6.72-6.76(m, 2H), 6.93-6.98 (m, 2H), 7.00-7.08 (m, 4H), 7.31-7.47 (m, 5H). [M+H]Calc'd for C₂₄H₂₇NO, 346. Found, 346.

Preparation 117C: 4-(ethyl(4-isopropylphenyl)amino)phenol

The title compound was prepared in 85% yield from4-(benzyloxy)-N-ethyl-N-(4-isopropylphenyl)aniline according to theprocedure of Preparation 26B. [M+H] Calc'd for C₁₇H₂₁NO, 256 Found, 256.

Example 117:2-(4-(ethyl(4-isopropylphenyl)amino)phenoxy)pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 5% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-(ethyl(4-isopropylphenyl)amino)phenol according to the procedure forthe preparation of Example 1. ¹H NMR (400 MHz, CDCl₃): δ 1.23-1.28 (m,9H), 2.87-2.94 (m, 1H), 3.77 (q, J=6.8 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H),7.05-7.11 (m, 4H), 7.20 (d, J=8.0 Hz, 2H), 8.01 (brs, 1H), 8.59 (brs,1H), 8.93 (s, 1H), 9.69 (brs, 1H). [M+H] Calc'd for C₂₄H₂₄N₄O₂, 401.Found, 401.

Preparation 118A: N-(4-isopropylphenyl)tetrahydro-2H-pyran-4-amine

To a solution of compound 4-isopropylaniline (1.0 g, 7.4 mmol),dihydro-2H-pyran-4(3H)-one (1.5 g, 14.8 mmol) in DMF (10 mL) was addedAcOH (2 mL). After stirring at RT for 30 min, the reaction mixture wascooled to 0° C., and sodium triacetoxyborohydride (3.2 g, 14.8 mmol) wasadded slowly. The mixture was stirred at RT for 2 h and then cooled to0° C., quenched with Na₂CO₃ solution and extracted with EA (2×20 mL).The combined organics were washed with water (2×10 mL), washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bysilica column chromatography (PE:EA=10:1) to give 1.5 g (93%) of thetitle compound as colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.20 (d,J=7.2 Hz, 6H), 1.39-1.53 (m, 2H), 2.00-2.05 (m, 2H), 2.75-2.85 (m, 1H),3.41-3.55 (m, 3H), 3.96-4.03 (m, 2H), 6.57 (d, J=8.4 Hz, 2H), 7.04 (d,J=8.4 Hz, 2H). [M+H] Calc'd for C₁₄H₂₁NO, 220. Found, 220.

Preparation 118B:4-((4-isopropylphenyl)(tetrahydro-2H-pyran-4-yl)amino)phenol

The title compound was prepared in 30% yield fromN-(4-isopropylphenyl)tetrahydro-2H-pyran-4-amine according to theprocedure of Preparation 5A. [M+H] Calc'd for C₂₀H₂₅NO₂, 312 Found, 312.

Example 118:2-(4-((4-isopropylphenyl)(tetrahydro-2H-pyran-4-yl)amino)phenoxy)pyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in 8% yield from2-chloro-pyrido[3,4-d]pyrimidin-4-ol and4-((4-isopropylphenyl)(tetrahydro-2H-pyran-4-yl)amino)phenol accordingto the procedure for the preparation of Example 1. ¹H NMR (400 MHz,CDCl₃): δ 1.28 (d, J=6.8 Hz, 6H), 1.54-1.66 (m, 2H), 1.91-1.92 (m, 2H),2.90-2.97 (m, 1H), 3.50-3.57 (m, 2H), 4.01-4.12 (m, 3H), 6.71 (d, J=9.2Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.08 (d, J=9.2 Hz, 2H), 7.24 (d, J=8.4Hz, 2H), 8.02 (d, J=4.8 Hz, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.90 (s, 1H),9.09 (brs, 1H). [M+H] Calc'd for C₂₇H₂₈N₄O₃, 457. Found, 457.

II. Biological Evaluation Example 1: In Vitro Enzyme Inhibition Assay

This assay determines the ability of a test compound to inhibit JMJD2Cdemethylase activity. Baculovirus expressed JMJD2C (GenBank Accession#BC143571, AA 2-372) was purchased from BPS Bioscience (Cat#50105).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide(Anaspec cat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of 0.9nM JMJD2C to initiate the reaction. The reaction mixture was incubatedat room temperature for 30 minutes, and terminated by the addition of 6μl of 5 mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylaseactivity was quantified and the respective IC₅₀ value was determined.Table 3 provides the IC₅₀ values of various compounds disclosed herein.

TABLE 3 JMJD2C Example Name IC₅₀ 1 2-[4-(methyl-pyridin-2-yl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 22-(1-methyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol B 32-(1-phenethyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol B 42-(1-benzyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol B 52-[4-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 62-[4-(benzyl-methyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 72-[3-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol C 82-(1-benzyl-1H-indol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol C 92-[3-(benzyl-methyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol C 102-[3-fluoro-4-(methyl-phenyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-olB 11 2-(1-benzyl-1H-indazol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol B 122-(2-benzyl-2H-indazol-6-yloxy)-pyrido[3,4-d]pyrimidin-4-ol B 132-{4-[methyl(2-phenylethyl)amino]phenoxy}pyridino[3,4-d]pyrimidin-4-ol B14 2-[2-benzyl-2H-indazol-5-yloxy]pyridino[3,4-d]pyrimidin-4-ol B 152-(1-benzyl-1H-indazol-5-yloxy)-pyridino[3,4-d]pyrimidin-4-ol B 162-{4-[(4-methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-olB 172-{4-[(3-methoxy-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-olB 18 2-{4-[methyl-(4-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4-B d]pyrimidin-4-ol 192-{4-[methyl-(3-morpholin-4-yl-phenyl)-amino]-phenoxy}-pyrido[3,4- Bd]pyrimidin-4-ol 202-[4-(methyl-p-tolyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 212-[4-(methyl-m-tolyl-amino)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 222-(4-{methyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amino}-phenoxy)- Apyrido[3,4-d] pyrimidin-4-ol 232-(4-{[4-(4-amino-piperidin-1-yl)-phenyl]-methyl-amino}-phenoxy)- Bpyrido[3,4-d]pyrimidin-4-ol 24N-[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]- BN-methyl-2-phenyl-acetamide 252-[4-(3-phenyl-piperidin-1-yl)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 262-[4-(2-phenyl-morpholin-4-yl)-phenoxy]-pyrido[3,4-d]pyrimidin-4-ol B 272-{4-[methyl-(5-morpholin-4-yl-pyridin-3-yl)-amino]-phenoxy}-pyrido B[3,4-d]pyrimidin-4-ol 282-{4-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-amino]- Aphenoxy}-pyrido[3,4-d]pyrimidin-4-ol 292-(4-{[4-(2-methoxy-1-methyl-ethyl)-phenyl]-methyl-amino}-phenoxy)- Bpyrido[3,4-d]pyrimidin-4-ol 303-(4-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-B phenyl)-butyronitrile 312-(1-cyclopentyl-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol C 322-(1-phenyl-2,3-dihydro-1H-indol-5-yloxy)-pyrido[3,4-d]pyrimidin-4-ol B332-(1-phenyl-1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrido[3,4-d]pyrimidin-4-olC 34 2-{4-[(5-isopropyl-pyridin-2-yl)-methyl-amino]-phenoxy}-pyrido A[3,4-d]pyrimidin-4-ol 352-{4-[(4-isopropyl-3-morpholin-4-yl-phenyl)-methyl-amino]-phenoxy}- Bpyrido[3,4-d]pyrimidin-4-ol 362-(4-{[4-(1-methoxy-ethyl)-phenyl]-methyl-amino}-phenoxy)- Bpyrido[3,4-d]pyrimidin-4-ol 372-(4-{[4-(2-amino-1-methyl-ethyl)-phenyl]-methyl-amino}- Aphenoxy)-pyrido[3,4-d]pyrimidin-4-ol 382-{4-[(4-{2-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-ethyl}-phenyl)- Bmethyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-ol 392-(4-{[4-(1-cyclopropyl-ethyl)-phenyl]-methyl-amino}-phenoxy)- Cpyrido[3,4-d]pyrimidin-4-ol 403-{[4-(4-hydroxy-pyrido[3,4-d]pyrimidin-2-yloxy)-phenyl]-methyl-amino}-benzonitrileB 412-(4-{methyl-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amino}-phenoxy)-A pyrido[3,4-d]pyrimidin-4-ol 422-{4-[(4-cyclopropyl-phenyl)-methyl-amino]-phenoxy}-pyrido[3,4-d]pyrimidin-4-olB 432-[4-[methyl-(5-methylpyridin-2-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 442-[4-[4-(dimethylamino)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olA 45 4-[3-[4-(4-hydroxypyrido[3,4-d]pyrimidin-2-yl)oxy-N-methylanilino]B phenyl]-1-methylpiperazin-2-one 462-[4-[N-methyl-4-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 472-[4-[3-(dimethylamino)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 482-[4-(N-methyl-3-pyrrolidin-1-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 492-[4-(N-methyl-4-pyrrolidin-1-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olC 502-[4-[3-(4-aminopiperidin-1-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olA 512-[4-[methyl-[(1S)-1-phenylethyl]amino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 522-[4-[methyl-[(1R)-1-phenylethyl]amino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 532-[4-(3-fluoro-N,4-dimethylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol B54 2-[4-(3-phenylpyrrolidin-1-yl)phenoxy]pyrido[3,4-d]pyrimidin-4-ol C552-[4-(N,4-dimethyl-3-morpholin-4-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 562-[4-(N-methyl-3-methylsulfonylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 572-[4-(N-methyl-4-methylsulfonylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 582-[4-[3-(3-aminopiperidin-1-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olA 592-[4-(4-ethyl-N-methyl-3-morpholin-4-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olA 602-[4-[4-ethyl-N-methyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 612-[4-[methyl-(2-morpholin-4-ylpyridin-4-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-olA 622-[4-[2,3-dihydro-1H-inden-1-ylmethyl(methyl)amino]phenoxy]pyrido[3,4- Bd]pyrimidin-4-ol 632-[4-[N-methyl-4-(2-methylpropyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 642-[4-[4-(2-hydroxypropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 652-[4-[3-[2-(dimethylamino)ethoxy]-4-ethyl-N-methylanilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 662-[4-[4-ethyl-3-(2-methoxyethoxy)-N-methylanilino]phenoxy]pyrido[3,4- Cd]pyrimidin-4-ol 672-[4-[4-(1-methoxy-2-methylpropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-C d]pyrimidin-4-ol 682-[4-[4-(1-hydroxy-2-methylpropan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-B d]pyrimidin-4-ol 692-[4-(N-methyl-4-propylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol C 702-[4-[N-methyl-4-[1-(methylamino)propan-2-yl]anilino] Aphenoxy]pyrido[3,4-d]pyrimidin-4-ol 712-[4-[4-(4-aminobutan-2-yl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olA 722-[4-[N-methyl-4-[4-(methylamino)butan-2-yl]anilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 732-[4-[N-methyl-4-(2,2,2-trifluoroethoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 742-[4-[N-methyl-4-(2-methylpropoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 752-[4-[4-(2,2-dimethylpropoxy)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 762-[4-[4-(cyclopropylmethyl)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 772-[4-[4-[(2S)-butan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 782-[4-[4-[(2R)-butan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 792-[4-[N-methyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olA 80 2-[4-(N-ethylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol B 814-[4-(4-hydroxypyrido[3,4-d]pyrimidin-2-yl)oxy-N-methylanilino]benzonitrileB 822-[4-[methyl-(2-methylindazol-5-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 83 2-[4-(N,3,4-trimethylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol C84 2-[4-(4-ethyl-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol B852-[4-(N-methyl-4-propan-2-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olC 862-[4-[N-methyl-3-(trifluoromethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 872-[4-[N-methyl-4-(trifluoromethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 882-[4-[N-methyl-3-(4-methyl-1,4-diazepan-1-yl)anilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 892-[4-[N-methyl-3-[methyl-(1-methylpiperidin-4-yl)amino]anilino]phenoxy]A pyrido[3,4-d]pyrimidin-4-ol 902-[4-[N,3-dimethyl-5-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 912-[1-(oxan-4-yl)indol-5-yl]oxypyrido[3,4-d]pyrimidin-4-ol B 922-[4-(4-tert-butyl-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-ol B932-[4-(N-methyl-3-propan-2-ylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 94 2-[4-(4-chloro-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 95 2-[4-(3-chloro-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olC 96 2-[4-(3-fluoro-N-methylanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 972-[4-[(5-ethylpyridin-2-yl)-methylamino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 982-[4-[4-(3,6-dihydro-2H-pyran-4-yl)-N-methylanilino]phenoxy]pyrido[3,4-C d]pyrimidin-4-ol 992-[4-[N-methyl-4-(oxan-4-yl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 1002-[4-[4-[1-(2-methoxyethylamino)propan-2-yl]-N-methylanilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 1012-[4-[4-(cyclopropylmethoxy)-N-methylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 1022-[4-[N-(2-methoxyethyl)-4-propan-2-ylanilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 103 2-(1-phenylindol-5-yl)oxypyrido[3,4-d]pyrimidin-4-ol C 1042-(1-piperidin-4-ylindol-5-yl)oxypyrido[3,4-d]pyrimidin-4-ol A 1052-[4-[N,4-dimethyl-3-(4-methylpiperazin-1-yl)anilino]phenoxy]pyrido[3,4-A d]pyrimidin-4-ol 1062-[4-[N-methyl-4-(2,2,2-trifluoroethyl)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 1072-[4-[N-methyl-4-[1-(trifluoromethyl)cyclopropyl]anilino]phenoxy]pyrido[3,4-C d]pyrimidin-4-ol 1082-[4-[N-methyl-4-(1,1,1-trifluoropropan-2-yl)anilino]phenoxy]pyrido[3,4-d]B pyrimidin-4-ol 1092-[4-[methyl-(6-propan-2-ylpyridin-3-yl)amino]phenoxy]pyrido[3,4-d]pyrimidin-4-olB 1102-[4-[N-methyl-4-(trifluoromethoxy)anilino]phenoxy]pyrido[3,4-d]pyrimidin-4-olC 1112-[4-(N-methyl-4-propan-2-yloxyanilino)phenoxy]pyrido[3,4-d]pyrimidin-4-olB 114 2-{4-[(4-isopropyl-phenyl)-(2,2,2-trifluoro-ethyl)-amino]- Bphenoxy}-pyrido[3,4-d]pyrimidin-4-ol 1152-(4-{[4-(3-dimethylamino-1-methyl-propyl)-phenyl]-methyl-amino}-phenoxy)-A pyrido[3,4-d]pyrimidin-4-ol 116(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methyl-[4-(4-methyl-pyrido[3,4-B d]pyrimidin-2-yloxy)-phenyl]-amine 1172-(4-(ethyl(4-isopropylphenyl)amino)phenoxy)pyrido[3,4-d]pyrimidin-4-olC 1182-(4-((4-isopropylphenyl)(tetrahydro-2H-pyran-4-yl)amino)phenoxy)pyrido[3,4-B d]pyrimidin-4-ol Note: Biochemical assay IC₅₀ data are designatedwithin the following ranges: A: ≤0.10 μM B: >0.10 μM to ≤1.0 μM C: >1.0μM to ≤10 μM D: >10 μM

Example 2: In Vitro Cell-Based Assay

The primary cellular assay for JMJD2C inhibition is an assay whichmeasures cellular proliferation via Bromodeoxyuridine (BrdU)incorporation after 168 hours of compound incubation. Cell lines testedinclude the JMJD2C gene amplified cell line KYSE-150. This is aquantitative ELISA assay measuring DNA incorporation of BrdU duringS-phase as a direct readout of cellular proliferation.

Assay Principle: This is a colorimetric immunoassay for thequantification of cell proliferation. Cells treated for 168 hours withtest compounds are assayed for their ability to go through S-phase as ameasure of their proliferative potential.

Assay Method: The human KYSE-150 (SMAD4 mut, TP53 mut) esophagealcarcinoma cell line was seeded at 2,000 cells/well on a 96-well tissueculture treated plate. After an overnight incubation, cells were treatedwith compound in an 11-point dilution series with final concentrationsranging from 100 μM to 2 nM. Cells were then incubated in the presenceof compound for 168 hours. After compound incubation the cells wereassayed using a BrdU Cell Proliferation ELISA (Roche). The cells werefirst incubated with BrdU labeling reagent for 2 hours. After 2 hours,the BrdU incorporated cells were fixed and denatured, probed with ananti-BrdU-Peroxidase antibody for 1.5 hours and washed. Finally, atetramethylbenzidine peroxidase substrate was added to each well for 15minutes followed by a H₂SO₄ stop solution. The plate was read at 450 nm,and the raw optical density data was transferred into XLFit (IDBS) forIC₅₀ calculation using the formula:fit=(D+((Vmax*(x^n))/((x^n)+(Km^n))))

Table 4 provides the cellular IC₅₀ values of various compounds disclosedherein.

TABLE 4 Ex. Cellular IC₅₀ 1 C 2 A 3 B 4 B 5 B 6 A 7 C 12 C 13 C 15 C 19B 23 C 24 D 26 D 27 D 29 B 30 A 32 C 36 B 37 D 38 A 39 A 40 D 41 C 42 B43 B 44 D 45 D 46 D 47 B 48 D 49 B 50 D 51 C 52 C 53 B 54 D 55 C 56 D 57D 58 D 59 D 60 D 61 D 62 C 64 B 65 D 66 C 67 A 68 B 69 A 70 D 71 C 72 D73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 B 81 D 82 D 83 B 84 A 85 A 86 B 87B 88 D 89 C 90 D 91 D 92 A 94 B 95 C 96 C 97 B 98 D 99 A 100 D 101 B 102B 103 D 104 D 105 C 106 A 107 A 108 A 109 C 110 B 111 B 115 D 117 ANote: Cell assay IC₅₀ data are designated within the following ranges:A: ≤0.10 μM B: >0.10 μM to ≥1.0 μM C: >1.0 μM to ≥10 μM D: >10 μM

Example 3: In Vivo Xenograph Study

Time release pellets containing 0.72 mg 17-13 Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 L/animal) on theright flank 2-3 days post pellet implantation and tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or compound daily for 4 weeks. Tumorvolume and body weight are monitored bi-weekly throughout the study. Atthe conclusion of the treatment period, plasma and tumor samples aretaken for pharmacokinetic and pharmacodynamic analyses, respectively.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weight of a compound of Formula(I) or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A method of treating a histone demethylase-associatedesophageal and breast cancer in a subject comprising administering atherapeutically effective dose of a compound of Formula (IIIa)

wherein the compound of Formula (IIIa) includes pharmaceuticallyacceptable salts thereof, wherein: X is halogen and n is 0 or 1; Y ishydrogen or C₁-C₃alkyl; Z is halogen, —OH, —NH₂, —CN, —SO₂, CF₃, alkyl,alkoxy, alkylamino, optionally substituted 3 membered carbocyclyl,optionally substituted 5-7 membered heterocyclyl comprising 1-2heteroatoms selected from N or O, or 6 membered heteroaryl comprising 1oxygen; and m is 0, 1, or
 2. 2. The method of claim 1, wherein n is 0.3. The method of claim 1, wherein Y is methyl.
 4. The method of claim 1,wherein m is
 1. 5. The method of claim 1, wherein carbocyclyl isoptionally substituted with CF₃.
 6. The method of claim 1, whereinhererocyclyl is optionally substituted with C₁ alkyl, amine, or oxo.